Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action XYNTHA temporarily replaces the missing clotting factor VIII that is needed for effective hemostasis. Pharmacodynamics The activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia. Determination of aPTT is a conventional in vitro assay for biological activity of factor VIII. Treatment with XYNTHA normalizes the aPTT over the effective dosing period. Pharmacokinetics The pharmacokinetic parameters of XYNTHA in 30 previously treated adult patients (PTP) 12 to 60 years old, who received a single infusion of 50 IU/kg XYNTHA are summarized in Table 3. In addition, 25 of the same subjects later received a single infusion of 50 IU/kg of XYNTHA for a 6-month follow-up pharmacokinetic study. The parameters were comparable between baseline and 6 months, indicating no time-dependent changes in the pharmacokinetics of XYNTHA. In a separate study, 8 of 30 subjects at least 12 years old with hemophilia A undergoing elective major surgery received a single 50 IU/kg infusion of XYNTHA. The pharmacokinetic parameters in these subjects are also summarized in Table 3. Table 3: Mean ± SD XYNTHA Pharmacokinetic Parameters in Previously Treated Patients with Hemophilia A after Single 50 IU/kg Dose Parameter Initial Visit (n = 30) Month 6 (n = 25) Pre-surgery (n=8) Cmax (IU/mL) 1.08 ± 0.22 1.24 ± 0.42 1.08 ± 0.24 AUC∞ (IU-hr/mL) 13.5 ± 5.6 15.0 ± 7.5 16.0 ± 5.2 t½ (hr) 11.2 ± 5.0 11.8 ± 6.2* 16.7 ± 5.4 CL (mL/hr/kg) 4.51 ± 2.23 4.04 ± 1.87 3.48 ± 1.25 Vss (mL/kg) 66.1 ± 33.0 67.4 ± 32.6 69.0 ± 20.1 Recovery (IU/dL per IU/kg) 2.15 ± 0.44 2.47 ± 0.84 2.17 ± 0.47 Abbreviations: AUC = area under the plasma concentration-time curve from zero to infinity; C = peak concentration; t = plasma elimination half-life; CL = clearance; n = number of subjects; SD = standard deviation; Vss = volume of distribution at steady-state. * One subject was excluded from the calculation due to lack of a well-defined terminal phase. Table 4 shows the pharmacokinetic parameters of nine children; four aged 14 or 15 years of age, who are also included in the summary for the adults above, along with five children aged 3.7–5.8 years after single 50 IU/kg doses of XYNTHA. Compared to adults, the half-life of XYNTHA is shorter in children and the clearance (based on per kg body weight) is approximately 40% higher in children. Table 4: Mean ± SD XYNTHA Pharmacokinetic Parameters in Previously Treated Pediatric Patients with Hemophilia A after Single 50 IU/kg Dose Parameter Young Children (n=5) Adolescents (n=4) Age (min - max, yr)) 3.7 - 5.8 14 - 15 Cmax (IU/mL) 0.78 ± 0.34 0.97 ± 0.21 AUC∞ (IU-hr/mL) 12.2 ± 6.50 8.5 ± 4.0 t½ (hr) 8.3 ± 2.7 6.9 ± 2.4 CL (mL/hr/kg) 6.29 ± 4.87 6.62 ± 2.16 Vss (mL/kg) 66.9 ± 55.6 67.1 ± 13.6 Recovery (IU/dL per IU/kg) 1.52 ± 0.69 1.95 ± 0.41 Abbreviations: AUC∞ = area under the plasma concentration-time curve from zero to infinity; Cmax = peak concentration; t½ = plasma elimination half-life; CL = clearance; n = number of subjects; SD = standard deviation; Vss = volume of distribution at steady-state. Animal Toxicology And/Or Pharmacology Preclinical studies evaluating XYNTHA in hemophilia A dogs without inhibitors demonstrated safe and effective restoration of hemostasis. XYNTHA demonstrated a toxicological profile that was similar to the toxicological profile observed with the predecessor product. Toxicity associated with XYNTHA was primarily associated with anti-FVIII neutralizing antibody generation first detectable at 15 days of repeat dosing in high (approximately 735 IU/kg/day) level-dosed, non-human primates. Clinical Studies Safety And Efficacy Study In an open label safety and efficacy study (n=94), subjects received XYNTHA in a routine prophylaxis treatment regimen with on-demand treatment administered as clinically indicated. All 94 subjects were treated with at least one dose and all are included in the intent-to-treat (ITT) population. All subjects had been previously treated (previously treated patients or PTPs) with factor VIII. Eighty-nine (89) subjects accrued ≥ 50 exposure days (EDs). Median age for the 94 treated subjects was 24 years (mean 27.7 and range 12–60 years). All subjects had ≥ 150 previous exposure days with baseline FVIII activity level of ≤ 2%. Of the 94 subjects enrolled in this study, 30 evaluable subjects participated in a randomized crossover pharmacokinetics study. Twenty-five (25/30) of these subjects with FVIII:C ≤ 1% completed both the first (PK1) and the second (PK2) pharmacokinetic assessments [see CLINICAL PHARMACOLOGY].16 For routine prophylaxis, XYNTHA was administered at a dose of 30 ± 5 IU/kg 3 times a week with provisions for dose escalation based on pre-specified criteria. Seven dose escalations were prescribed for 6 subjects during the course of the study. Forty-three subjects (43/94 or 45.7%) reported no bleeding while on routine prophylaxis. The median annualized bleeding rate (ABR) for all bleeding episodes was 1.9 (mean 3.9, range 0–42.1). Fifty-three subjects (53/94) received XYNTHA on-demand treatment for a total of 187 bleeding episodes. Seven of these bleeding episodes occurred in subjects prior to switching to a prophylaxis treatment regimen. One hundred ten of 180 bleeds (110/180 or 61.1%) occurred ≤ 48 hours after the last dose and 38.9% (70/180 bleeds) occurred > 48 hours after the last dose. The majority of bleeds reported to occur ≤ 48 hours after the last prophylaxis dose were traumatic (64/110 bleeds or 58.2%). Forty-two bleeds (42/70 or 60%) reported to occur > 48 hours after the last prophylaxis dose were spontaneous. The on-demand treatment dosing regimen was determined by the investigator. The median dose for on-demand treatment was 30.6 IU/kg (range 6.4 to 74.4 IU/kg). The majority of bleeding episodes (173/187 or 92.5%) resolved with 1 or 2 infusions (Table 5). Subjects rated the outcomes of infusions on a pre-specified four (4) point hemostatic efficacy scale. One hundred thirty-two of 187 bleeding episodes (132/187 or 70.6%) treated with XYNTHA were rated excellent or good in their response to initial treatment, 45 (24.1%) were rated moderate. Five (2.7%) were rated no response, and 5 (2.7%) were not rated. Table 5: Summary of Response to Infusions to Treat New Bleeding Episode by Number of Infusions Needed for Resolution Number of Infusions (%) Response to 1st Infusion 1 2 3 4 > 4 Total Number of Bleeds Excellent* 42 (95.5) 2 (4.5) 0 (0.0) 0 (0.0) 0 (0.0) 44 Good† 69 (78.4) 16 (18.2) 3 (3.4) 0 (0.0) 0 (0.0) 88 Moderate‡ 24 (53.3) 16 (35.6) 2 (4.4) 0 (0.0) 3 (6.7) 45 No Response§ 0 (0.0) 0 (0.0) 2 (40.0) 2 (40.0) 1 (20.0) 5 Not Assessed 4 (80.0) 0 (0.0) 0 (0.0) 1 (20.0) 0 (0.0) 5¶ Total 139 (74.3) 34 (18.2) 7 (3.7) 3 (1.6) 4 (2.1) 187 Excellent: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with no additional infusion administered. †Good: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with at least one additional infusion administered for complete resolution of the bleeding episode. ‡Moderate Probable or slight improvement starting after 8 hours following the infusion, with at least one additional infusion administered for complete resolution of the bleeding episode. §No Response: No improvement at all between infusions or during the 24 hour interval following an infusion, or condition worsens. ¶Includes one infusion with commercial FVIII that occurred before routine prophylaxis began. Perioperative Management Study In an open-label study (n=30) for surgical prophylaxis in subjects with hemophilia A, XYNTHA was administered to 25 efficacy-evaluable PTPs with severe or moderately severe (FVIII:C ≤ 2%) hemophilia A undergoing major surgical procedures (11 total knee replacements, 1 hip replacement, 5 synovectomies, 1 left ulnar nerve transposition release, 1 ventral hernia repair/scar revision, 1 knee arthroscopy, 1 revision and debridement of the knee after a total knee replacement, 1 hip arthroplasty revision, 1 stapes replacement, 1 ankle arthrodesis, and 1 pseudotumor excision).17 The results of the hemostatic efficacy ratings for these subjects are presented in Table 6. Investigator's ratings of efficacy at the end of surgery and at the end of the initial postoperative period were “excellent” or “good” for all assessments. Intraoperative blood loss was reported as “normal” or “absent” for all subjects. Thirteen of the subjects (13/25 or 52%) had blood loss in the postoperative period. The postoperative blood loss was rated as “normal” for ten of these cases while three cases were rated “abnormal” (1 due to hemorrhage following surgical trauma to the epigastric artery, 1 due to an 800 mL blood loss after hip replacement surgery, and 1 after an elbow synovectomy where the blood loss could not be measured by the investigator). Table 6: Summary of Hemostatic Efficacy Time of Hemostatic Efficacy Assessment Excellent* Good† Number of subjects End of surgery 18 (72%) 7 (28%) 25 End of initial postoperative period‡ 23 (92%) 2 (8%) 25 Excellent : Achieved hemostasis comparable to that expected after similar surgery in a patient without hemophilia. †Good: Prolonged time to hemostasis, with somewhat increased bleeding compared with that expected after similar surgery in a patient without hemophilia. ‡End of initial postoperative period is date of discharge or postoperative Day 6, whichever occurs later. REFERENCES 1. Nilsson IM, Berntorp EE and Freiburghaus C. Treatment of patients with factor VIII and IX inhibitors. Thromb Haemost. 1993;70(1):56–59. 3. Juhlin F. Stability and Compatibility of Reconstituted Recombinant Factor VIII SQ, 250 IU/ml, in a System for Continuous Infusion. Pharmacia Document 9610224, 1996. 15. Mann KG and Ziedens KB. Overview of Hemostasis. In: Lee CA, Berntorp EE and Hoots WK, eds. Textbook of Hemophilia. USA, Blackwell Publishing; 2005:1–4. 16. Recht M, Nemes L, Matysiak M et al. Clinical Evaluation of Moroctocog Alfa (AF-CC), a New Generation of B-Domain Deleted Recombinant Factor VIII (BDDrFVIII) for Treatment of Haemophilia A: Demonstration of Safety, Efficacy and Pharmacokinetic Equivalence to Full-length Recombinant Factor VIII. Haemophilia 2009; 1–12. 17. Windyga J, Rusen L, Gruppo R, et al. BDDrFVIII (Moroctocog alfa [AF-CC]) for surgical haemostasis in patients with haemophilia A: results of a pivotal study. Haemophilia. 2010 Sep 1;16(5):731-9.

CLINICAL PHARMACOLOGY Factor VIII is the specific clotting factor deficient in patients with hemophilia A (classical hemophilia). The administration of ReFacto® (antihemophilic factor) Antihemophilic Factor (Recombinant) increases plasma levels of factor VIII activity and can temporarily correct the in vitro coagulation defect in these patients. Activated factor VIII acts as a cofactor for activated factor IX accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed. Factor VIII activity is greatly reduced in patients with hemophilia A and therefore replacement therapy is necessary. In a crossover pharmacokinetic study of eighteen (18) previously treated patients using the chromogenic assay, the circulating mean half-life for ReFacto (antihemophilic factor) was 14.8 ± 5.6 hours (range 7.6-28.5 hours), which was not statistically significantly different from plasma-derived Antihemophilic Factor (Human) (pdAHF), which had a mean half-life of 13.7 ± 3.7 hours (range 8.8-25.1 hours). Mean incremental recovery (K-value) of ReFacto (antihemophilic factor) in plasma was 2.4 ± 0.4 IU/dL per IU/kg (range 1.9-3.3 IU/dL per IU/kg). This was comparable to the mean incremental recovery observed in plasma for pdAHF which was 2.3 ± 0.3 IU/dL per IU/kg (range 1.7-2.9 IU/dL per IU/kg). Results of a comparative study that evaluated the effect of phospholipids on the one-stage clotting and chromogenic assays showed that the one-stage clotting assay gave results that were approximately 50% of the values obtained with the chromogenic assay (see DOSAGE AND ADMINISTRATION). In 2 additional clinical studies, pharmacokinetic parameters were evaluated for previously treated patients [PTPs] and previously untreated patients [PUPs]. In PTPs (n=101; median age 26 ± 12 years) ReFacto (antihemophilic factor) had a mean incremental recovery at Week 0 of 2.4 ± 0.4 IU/dL per IU/kg (range 1.1-3.8 IU/dL per IU/kg). In measurements over 4 years of use (Month 3 [n=90], Month 6 [n=87], Month 12 [n=88], Month 24 [n=70], Month 36 [n=64], and Month 48 [n=52]), mean incremental recovery was reproducible and ranged from 2.3 to 2.5 IU/dL per IU/kg. A subset of 37 study subjects had evaluable pharmacokinetic profiles at both baseline and Month 12 (Table 1). The 90% confidence intervals for the ratios of the mean values of Month 12-to-baseline AUCT, AUC∞, and K-value were well within the bioequivalence window of 80% to 125%, demonstrating the stability of these pharmacokinetic parameters over 1 year. In PUPs (n=59; median age 10 ± 8.3 months) ReFacto (antihemophilic factor) had a lower mean incremental recovery at Week 0 of 1.5 ± 0.6 IU/dL per IU/kg (range 0.2-2.8 IU/dL per IU/kg) as compared to PTPs. The mean incremental recovery for PUPs was stable over time (5 visits during a 2-year period) and ranged from 1.5 to 1.8 IU/dL per IU/kg of ReFacto (antihemophilic factor) . Population pharmacokinetic modeling using data from 44 PUPs led to a mean estimated half-life of ReFacto (antihemophilic factor) in PUPs of 8.0 ± 2.2 hours. TABLE 1. MEAN FACTOR VIII PHARMACOKINETIC PARAMETERS FOR 37 PTPS WITH BOTH BASELINE AND MONTH 12 PHARMACOKINETIC PROFILES FOLLOWING A RAPID INFUSION OF REFACTO (antihemophilic factor) AT A DOSE OF 50 IU/KG Parameter Cmax (IU/mL) AUCT (hr*IU/mL) Half- life (hr) AUC∞ (hr*IU/mL) Clearance (mL/hr/kg) Mean Residence Time (hr) Vss (mL/kg) K-value (IU/dL/IU/kg) Baseline Mean 1.17 13.6 10.6 15.4 3.53 15.0 50.9 2.34 SD 0.24 3.4 2.5 4.5 1.03 3.4 13.0 0.49 Min 0.55 6.0 6.8 7.6 1.78 9.8 36.9 1.10 Max 1.90 21.1 17.2 28.1 6.60 24.7 99.0 3.80 Parameter Cmax (IU/mL) AUCT (hr*IU/mL) Half-life (hr) AUC∞ (hr*IU/mL) Clearance (mL/hr/kg) Mean Residence Time(hr) Vss (mL/kg) K-value (IU/dL/IU/kg) Month 12 Mean 1.20 14.0 11.4 16.5 3.37 16.1 51.1 2.40 SD 0.29 4.7 3.5 5.7 1.08 4.6 11.4 0.58 Min 0.84 7.8 6.6 8.8 1.49 9.7 21.3 1.67 Max 2.31 32.4 20.1 33.5 5.66 27.8 83.2 4.61 The efficacy of ReFacto (antihemophilic factor) was evaluated in uncontrolled phase 3 studies of 113 PTPs and 101 PUPs who received ReFacto (antihemophilic factor) for on-demand treatment, routine prophylaxis, and/or surgical prophylaxis and were followed for up to 6 years. Hemostatic efficacy was rated on an ordinal scale of excellent, good, fair, and none. In 112 of 113 PTPs treated on demand, a total of 10,882 bleeding episodes were reported, with a median of 77.5 bleeding episodes per study subject. Of these, the hemostatic efficacy of ReFacto (antihemophilic factor) was assessed following the first infusion for treatment of 10,445 bleeding episodes: 9944 (95%) were rated excellent or good in their response to treatment, 429 (4%) were rated fair, and 72 (0.7%) were rated as having no response; 4% (437/10,882) of the bleeding episodes were not rated. Of the 10,882 bleeding episodes, 7981 (73%) were managed with a single infusion, 1612 (15%) required 2 infusions, 623 (6%) required 3 infusions, and 666 (6%) required 4 or more infusions for satisfactory resolution. The mean dose per infusion was 31 IU/kg. In 100 of 101 PUPs treated on demand, a total of 2715 bleeding episodes were reported with a median of 19.5 bleeding episodes per study subject. Of these, the hemostatic efficacy of ReFacto (antihemophilic factor) was assessed following the first infusion for treatment of 2604 bleeding episodes: 2459 (94%) were rated excellent or good in their response to treatment, 142 (5%) were rated fair, and 3 (0.1%) were rated as having no response; 4% (111/2,715) of the bleeding episodes were not rated. Of the 2715 bleeding episodes, 1794 (66%) were managed with a single infusion, 502 (19%) required 2 infusions, 229 (8%) required 3 infusions, and 190 (7%) required 4 or more infusions for satisfactory resolution. The mean dose per infusion was 51 IU/kg. All were treated successfully on an on-demand basis or for the reduction of bleeding episodes except for one PTP and two PUPs who discontinued ReFacto (antihemophilic factor) treatment and switched to another product after the development of inhibitors. Bleeding episodes included hemarthroses, and bleeding in soft tissue, muscle, and other anatomical sites. One of 113 previously treated patients (PTPs) who were evaluated for efficacy in bleeding episodes developed a high titer inhibitor. The patient was noted initially at a local laboratory to have a treatment-emergent low titer inhibitor (1.2 BU) at 98 exposure days which was confirmed at 2 BU at the central laboratory at 113 exposure days. After 18 months on continued treatment with ReFacto (antihemophilic factor) , the inhibitor level rose to nearly 13 BU and a bleeding episode failed to respond to ReFacto (antihemophilic factor) treatment. In this study the incidence of inhibitor development to factor VIII using ReFacto (antihemophilic factor) is similar to that reported for other factor VIII products1-4. ReFacto (antihemophilic factor) has been studied in short-term routine prophylaxis. In uncontrolled phase 3 clinical trials, a mean dose of 27 ± 11 IU/kg per infusion in PTPs (n=85) and a mean dose of 49 ± 17 IU/kg per infusion in PUPs (n=45) was given repeatedly at variable intervals (for PTPs: median 94 weeks, range 3-296 weeks; for PUPs: median 61 weeks, range 2-222 weeks). In PTPs and PUPs, the mean rate of spontaneous musculoskeletal bleeding episodes was lower during periods of routine prophylaxis. PTPs (n=85) had a mean of 10 bleeding episodes (spontaneous and injury-related) per year during the prophylactic periods compared to a mean of 25 bleeding episodes per year during on-demand periods. PUPs (n=45) had a mean of 6 bleeding episodes (spontaneous and injury-related) per year during the prophylactic periods compared to a mean of 11 bleeding episodes per year during the on-demand periods. These non-randomized trial results should be interpreted with caution, as the investigators exercised their own discretion in deciding when and in whom prophylaxis was to be initiated and terminated. Management of hemostasis was evaluated in the surgical setting where 51 surgical procedures were performed in 39 study subjects. Procedures included orthopedic procedures (eg, total knee and hip replacements, removal of a left elbow pseudotumor, and arthroscopic synovectomy of the knee), inguinal hernia repair, epidural hematoma evacuation, ulnar nerve transposition, tonsillectomy, cholecystectomy with extirpation of hepatic abscess, and other minor procedures (eg, venous access catheter placement and explantation, and toenail removal). Of the 51 surgical procedures, 44 procedures were performed in 32 PTPs and 7 procedures were performed in 7 PUPs. In PTPs, the mean total dose for each of the 44 procedures was 104,064 IU administered over a mean of 22.1 exposure days; the mean dose per infusion (peri- and postoperative) was 37.4 IU/kg. In PUPs, the mean total dose for each of the 7 procedures was 21,766 IU administered over a mean of 12.4 exposure days; the mean dose per infusion (peri- and postoperative) was 93.5 IU/kg. Factor VIII activity levels were monitored at the local laboratory using a one-stage assay in 40 procedures and a chromogenic assay in 11 procedures. Circulatory factor VIII levels targeted to restore and maintain hemostasis were achieved regardless of which assay was used. For 50 of 51 rated surgical procedures, hemostatic efficacy was assessed as excellent or good in 99.6% (494/496) of assessments. The occurrence of neutralizing antibody (inhibitors) is well known in the treatment of patients with hemophilia A5,6,7. Thirty-two out of 101 PUPs (32%) developed an inhibitor: 16 out of 101 (16%) with a high titer ( > 5 BU) (12 of the 16 patients had peak values ≥ 10 BU) and 16 out of 101 (16%) with a low titer ( ≤ 5 BU). In this study the incidence of inhibitor development to factor VIII using ReFacto (antihemophilic factor) is similar to that reported for other factor VIII products5-10. REFERENCES 1. Kessler C, Sachse K. Factor VIII:C inhibitor associated with monoclonal-antibody purified FVIII concentrate. Lancet 1990; 335:1403. 2. Schwartz RS, Abildgaard CF, Aledort LM, et al. Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med 1990;323:1800-1805. 3. White GC II, Courter S, Bray GL, et al. A multicenter study of recombinant factor VIII (recombinate) in previously treated patients with hemophilia A. Thromb Haemost 1997;77(4):660-667. 4. Abshire TC, Brackmann HH, Scharrer I, et al. Sucrose formulated recombinant human antihemophilic Factor VIII is safe and efficacious for treatment of hemophilia A in home therapy: Results of a multicenter, international, clinical investigation. Thromb Haemost 2000;83(6):811-816. 5. Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII and factor IX inhibitors in hemophiliacs. Lancet. 1992;339:594-598. 6. Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor VIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood. 1994;83(9):2428-2435. 7. Lusher J, Arkin S, Abildgaard CF, Schwartz RS, Group TKPUPS. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. N Engl J Med. 1993;328:453-459. 8. Scharrer I, Bray G. Incidence of inhibitors in haemophilia A patients - a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Hemophilia 1999; 5:145. 9. Gruppo R, Chen H, Schroth P, et al. Safety and immunogenicity of recombinant factor VIII (Recombinate) in previously untreated patients: A 7.3 year update. Haemophilia 1998;4:228 (abstract no. 291, XXIII Congress of the WFH, The Hague). 10. Lusher J, Abildgaard C, Arkin S, et al. Human recombinant DNA-derived antihemophilic factor in the treatment of previously untreated patients with hemophilia A: Final report on a hallmark clinical investigation. J Thromb Haemost 2004;2:574-583.

CLINICAL PHARMACOLOGY Mechanism Of Action OBIZUR temporarily replaces the inhibited endogenous factor VIII that is needed for effective hemostasis in patients with acquired hemophilia A. Pharmacodynamics Patients with acquired hemophilia A (AHA) have normal factor VIII genes but develop autoantibodies against their own factor VIII (i.e., inhibitors). These autoantibodies neutralize circulating human factor VIII and create a functional deficiency of this procoagulant protein. AHA results in a prolonged clotting time as measured by the activated partial thromboplastin time (aPTT) assay, a conventional In vitro test for biological activity of factor VIII. Treatment with OBIZUR should normalize the aPTT during treatment; however aPTT normalization should not be used as a measure of efficacy. Clinical Studies The efficacy of OBIZUR for the treatment of serious bleeding episodes in subjects with acquired hemophilia A was investigated in a prospective, open-label trial (N=29). The trial was conducted in 18 Caucasian, 6 African-American, and 5 Asian subjects diagnosed with acquired hemophilia A (AHA), having auto-immune inhibitory antibodies to human factor VIII, and experiencing serious bleeding episodes that required hospitalization. Subjects with a prior history of bleeding disorders other than AHA, anti-porcine factor VIII antibody titer > 20 Bethesda Units (BU), or in whom the bleeding episode was judged likely to resolve on its own were excluded. One subject was considered evaluable at study entry; however, it was later determined that this subject did not have AHA, leaving 28 subjects evaluable for efficacy. An initial dose of 200 units per kg OBIZUR was administered to subjects for the treatment of life- or limb-threatening initial bleeding episodes. Patients were treated with OBIZUR until resolution of bleeding or dosing was continued at the physician's discretion according to the clinical assessment. These bleeding episodes included 19 intramuscular or joint bleeding episodes, 4 post-surgical bleeding episodes, 2 intracranial episodes, 2 surgeries, 1 retroperitoneal hemorrhage, and 1 periorbital bleed. Hemostatic response was assessed by the study site investigator at specified time points after initiation of OBIZUR treatment using a pre-specified rating scale that was based on subjective clinical assessments combined with objective factor VIII activity levels achieved. An assessment of effective or partially effective was considered as a positive response (see Table 2 for definitions). Table 2 : Response to OBIZUR Treatment Evaluation Assessment of efficacy Control of bleeding Clinical Assessment Factor VIII levels Response Effective bleeding stopped clinical control ≥ 50% positive Partially effective bleeding reduced clinical stabilization or improvement; or alternative reason for bleeding ≥ 20% positive Poorly effective bleeding slightly reduced or unchanged not clinically stable < 50% negative Not effective bleeding worsening Clinically deteriorating < 20% negative Of the 28 subjects evaluable for efficacy, all subjects had a positive response to treatment for the initial bleeding episodes at 24 hours after dosing. A positive response was observed in 95% (19/20) of subjects evaluated at 8 hours and 100% (18/18) at 16 hours. In addition to response to treatment, the overall treatment success was determined by the investigator based on his/her ability to discontinue or reduce the dose and/or dosing frequency of OBIZUR. A total of 24/28 (86%) had successful treatment of the initial bleeding episode. Of those subjects treated with OBIZUR as first-line therapy, defined as no immediate previous use of anti-hemorrhagic agents prior to the first OBIZUR treatment, 16/17 (94%) had eventual treatment success reported. Eleven subjects were reported to have received anti-hemorrhagics (eg. rFVIIa, activated prothrombin-complex concentrate, tranexamic acid) prior to first treatment with OBIZUR. Of these 11 subjects, eight had eventual successful treatment (73%). The median dose per infusion to successfully treat the primary bleeding episode was 133 units per kg and a median total dose of 1523 units per kg. In the initial 24 hour period, a median of 3 infusions (median dose 200 U/kg) were utilized in the clinical study. When treatment was required beyond 24 hours, a median of 10.5 infusions (median dose 100 U/kg) were given for a median of 6 days to control a bleeding episode.

CLINICAL PHARMACOLOGY Mechanism Of Action ADYNOVATE, a PEGylated form of recombinant antihemophilic factor (ADVATE), [see DESCRIPTION], temporarily replaces the missing coagulation factor VIII needed for effective hemostasis in congenital hemophilia A patients. ADYNOVATE exhibits an extended terminal half-life through pegylation of the parent molecule, ADVATE, which reduces binding to the physiological factor VIII clearance receptor (LRP1). Pharmacodynamics Hemophilia A is a disorder characterized by a deficiency of functional coagulation factor VIII, resulting in a prolonged, patient plasma clotting time as measured by the activated partial thromboplastin time (aPTT). Treatment with ADYNOVATE normalizes the aPTT over the effective dosing period. The administration of ADYNOVATE increases plasma levels of factor VIII and can temporarily correct the coagulation defect in hemophilia A patients. Pharmacokinetics The pharmacokinetics (PK) of ADYNOVATE was evaluated in a multi-center, prospective, open label study and compared with ADVATE in 26 subjects prior to initiation of prophylactic treatment with ADYNOVATE and in 22 subjects after 6 months of treatment with ADYNOVATE. A single dose of 45 IU/kg was utilized for both products. The PK parameters, as shown in Table 3, were based on plasma coagulation factor VIII activity measured by the one-stage clotting assay and are presented by age groups (adults and adolescents). The terminal plasma half-life of ADYNOVATE was 1.4- to 1.5-fold longer than that of ADVATE. Incremental recovery was comparable between both products. The PK parameters determined after 6 months of prophylactic treatment with ADYNOVATE were consistent with the initial parameter estimates. Table 3: Pharmacokinetic Parameters (Arithmetic Mean ±SD) PK Parameters 12 to < 18 years N = 8 ≥ 18 years N = 18 Terminal half-life [h] 13.43 ± 4.05 14.69 ± 3.79 MRT [h] 17.96 ± 5.49 20.27 ± 5.23 CL [mL/(kg-h)] 3.87 ± 3.31 (2.73 + 0.93)* 2.27 ± 0.84 Incremental Recovery [(IU/dL)/(IU/kg)] 2.12 ± 0.60 2.66 ± 0.68 AUC0-Inf [IU•h/dL] 1642±752 2264 ± 729 Vss [dL/kg] 0.56 ± 0.18 0.43 ± 0.11 Cmax [|U/dL] 95 ± 25 122 ± 29 Tmax [h] 0.26 ± 0.10 0.46 ± 0.29 Abbreviations: MRT: mean residence time; CL: clearance; CI: confidence interval; AUC: area under the curve; Vss: body weight adjusted volume of distribution at steady-state; Cmax: maximum observed activity; Tmax: time to reach the maximum concentration. * Estimated mean and SD calculated not including one subject whose clearance estimate was 11.8 mL/(kg·h). Median including all subjects is 2.78 mL/(kg·h). Pediatric Pharmacokinetics Pharmacokinetic profiles of ADYNOVATE have not been established in pediatric patients less than 12 years old. Clinical Studies The safety, efficacy, and PK of ADYNOVATE were evaluated in a multicenter, open-label, prospective, non-randomized, two-arm clinical trial that compared the efficacy of a twice weekly prophylactic treatment regimen to on-demand treatment and determined hemostatic efficacy in the treatment of bleeding episodes. A total of 137 male PTPs (12 to 65 years of age) with severe hemophilia A received at least one infusion with ADYNOVATE. Twenty-five of the 137 subjects were adolescents (12 to less than 18 years of age). Subjects received either prophylactic treatment (n = 120) with ADYNOVATE at a dose of 40-50 IU per kg twice weekly or on-demand treatment (n = 17) with ADYNOVATE at a dose of 10-60 IU per kg for a 6-month period. The mean (SD) dose per prophylaxis infusion was 44.4 (3.9) IU per kg with a median dosing interval of 3.6 days. There were 91 out of 98 (93%) subjects previously treated prophylactically prior to enrollment, who experienced a reduction in dosing frequency during routine prophylaxis in the study, with a median reduction of 33.7% (approximately one more day between doses). One hundred eighteen of 120 (98%) prophylaxis subjects remained on the starting recommended regimen without dose adjustment, and 2 subjects increased their dose to 60 IU/kg during prophylaxis due to bleeding in target joints. On-demand Treatment and Control of Bleeding Episodes A total of 518 bleeding episodes were treated with ADYNOVATE in the per-protocol population, i.e. dosed according to the protocol specific dosing requirements. Of these, 361 bleeding episodes (n=17 subjects) occurred in the on-demand arm and 157 (n=61 subjects) occurred in the prophylaxis arm. The median dose per infusion to treat all bleeding episodes in the per-protocol population was 29 (Q1: 20.0; Q3: 39.2) IU per kg. The median dose per infusion to treat a minor, moderate, or severe/major bleeding episode in the per-protocol population was 25.5 (Q1: 16.9; Q3: 37.6) IU/kg, 30.9 (Q1: 23.0; Q3: 43.1) IU/kg, or 36.4 (Q1: 29.0; Q3: 44.5) IU/kg, respectively. A total of 591 bleeding episodes were treated with ADYNOVATE in the treated population, which was identical to the safety analysis set of subjects assigned to routine prophylaxis or on-demand treatment with ADYNOVATE and who received at least one dose of the product. Of these, 361 bleeding episodes (n=17 subjects) occurred in the on-demand arm and 230 bleeding episodes (n=75 subjects) occurred in the routine prophylaxis arm. Efficacy in control of bleeding episodes is summarized in Table 4. Table 4: Summary of Efficacy in Control of Bleeding (Treated Population) Bleeding Episode Etiology All Joint Non-joint Number of bleeds treated 591 455 136 Number of infusions to treat bleeding episodes 1 infusions: 85.4% 85.9% 83.8% 2 infusions: 10.8% 10.8% 11.0% Total (1 or 2 infusions): 96.2% 96.7% 94.8% Rate of success to treat bleeding episodes* Excellent or good 95.3% 95.8% 93.4% * Excellent defined as full relief of pain and objective signs of bleeding cessation; Good defined as definite pain relief and/ or improvement in signs of bleeding; Fair defined as probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion. Required more than 1 infusion for complete resolution; None defined as no improvement or condition worsened. Routine Prophylaxis A total of 120 subjects (treated population) received a twice a week regimen in the prophylaxis arm, and an additional 17 subjects were treated episodically in the on-demand arm. In the treated population, the median [mean] annualized bleed rate (ABR) in the on-demand treatment arm was 41.5 [40.8] compared to 1.9 [4.7] while on a twice a week prophylaxis regimen (Table 5). In the per-protocol population, the median [mean] annualized bleed rate (ABR) in the on-demand treatment arm was 41.5 [40.8] compared to 1.9 [3.7] while on a twice a week prophylaxis regimen. Using a negative binomial model to estimate the ABR, there was a significant reduction in the ABR (p < 0.0001) for subjects in the prophylaxis arm compared to the on-demand arm. Table 5: Annualized Bleed Rate by Treatment for ≥ 12 years of age (Treated Population) Bleeding Episode Etiology On-Demand Treatment Routine Prophylaxis Treatment Median Mean (SD) Median Mean (SD) Overall 41.5 40.8 (16.3) 1.9 4.7 (8.6) Joint 38.1 34.7 (15.1) 0.0 2.9 (8.0) Non-Joint 3.7 6.1 (6.7) 0.0 1.8 (3.0) Spontaneous 21.6 26.0 (19.6) 0.0 2.9 (7.1) Traumatic 9.3 14.9 (15.3) 0.0 1.8 (3.1) In the treated population, the median [mean] ABR for the 23 adolescent subjects age 12 to < 18 years of age on routine prophylaxis was 2.1 [5.2] compared to a median [mean] ABR of 1.9 [4.6] for the 97 subjects 18 years and older. Reduction in ABR between the treatment arms was observed regardless of baseline subgroups examined, including age, presence or absence of target joints, and pre-study treatment regimen. The majority of the bleeding episodes during prophylaxis (95%) were of minor/moderate severity. Forty-five out of 120 subjects (38%) experienced no bleeding episodes and 68 out of 120 subjects (57%) experienced no joint bleeding episodes in the prophylaxis arm. Of those subjects who were compliant to regimen (per-protocol population), 40 out of 101 subjects (40%) experienced no bleeding episodes. All subjects in the on-demand arm experienced a bleeding episode, including a joint bleeding episode.

CLINICAL PHARMACOLOGY Mechanism Of Action ELOCTATE is a recombinant fusion protein that temporarily replaces the missing Coagulation Factor VIII needed for effective hemostasis. ELOCTATE contains the Fc 12 region of human immunoglobulin G1 (IgG1), which binds to the neonatal Fc receptor (FcRn). FcRn is part of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins by cycling them back into circulation and prolonging their plasma half-life. Pharmacodynamics Hemophilia A is a bleeding disorder characterized by a deficiency of functional coagulation Factor VIII, resulting in a prolonged, patient plasma clotting time as measured by the activated partial thromboplastin time (aPTT) assay. Treatment with ELOCTATE™ normalizes the aPTT over the effective dosing period. Pharmacokinetics The pharmacokinetics (PK) of ELOCTATE™ (rFVIIIFc) were evaluated in 28 subjects following a 10 minute intravenous infusion of a single dose of 50 IU/kg. The PK parameters (Table 4) were based on plasma FVIII activity measured by the one-stage clotting assay. The PK profile obtained at week 14, after repeated dosing, was comparable with the PK profile obtained after the first dose. The PK data demonstrate that ELOCTATE™ has a prolonged circulating half-life. Table 4: Pharmacokinetic Parameters (Arithmetic Mean, 95% CI) PK Parameters rFVIIIFc (95% CI) N=28 Cmax (IU/dL) 109 (102, 116) AUC/Dose (IU x h/dL per IU/kg) 54.1 (47.0, 61.1) Terminal half-life (h) 19.7 (17.4, 22.0) CL (mL/h/kg) 2.06 (1.78, 2.34) MRT (h) 26.1 (23.2, 28.9) Vss (mL/kg) 49.5 (46.9, 52.2) Incremental Recovery (IU/dL per IU/kg) 2.26 (2.13, 2.40) Time to 1% (days) 5.10 (4.54, 5.66) Abbreviations: CI = confidence interval; Cmax = maximum observed activity; AUC= area under the curve; MRT = mean residence time; CL = clearance; Vss = body weight adjusted volume of distribution at steady-state; Time to 1% = time after dose when FVIII activity has declined to 1 IU/dL above baseline. Pediatric and Adolescent Pharmacokinetics Pharmacokinetic (PK) parameters of ELOCTATE were determined for adolescents (ages 12 to 17 years) in the phase 3 study and for children (ages 2 to 5 years and 6 to 11 years) in an open-label, multi-center study of pediatric, previously treated patients. [see Pediatric Use] Table 5 presents the PK parameters calculated from the pediatric data of 48 subjects, less than 18 years of age, after receiving a single 50 IU/kg dose. Compared to adults and adolescents, body weight adjusted clearance was higher in children 2 to 5 years of age. These results indicate a need for dose adjustments in children 2 to 5 years of age. [see Pediatric Use] The PK evaluation of pediatric subjects, ages 6 to 17 years, showed that their PK profiles and arithmetic means of PK parameters are similar to those of adults. Therefore, for subjects 6 years and older, an age-based dose adjustment is not required. Table 5: Comparison of PK Parameters of ELOCTATE by Age PK Parameters1 Pediatric Study Phase 3 Study 2 to 5 Years N = 10 6 to 11 Years N = 27 12 to 17 Years N = 11 IR (IU/dL per IU/kg) 1.89 (1.75, 2.03) 2.44 (2.02, 2.85) 1.85 (1.58, 2.12) AUC/Dose (IU*h/dL per IU/kg) 28.3 (22.1, 34.5) 43.7 (35.1, 52.3) 38.7 (34.3, 43.1) t½ (h) 12.0 (9.55, 14.4) 14.6 (11.5, 17.7) 16.4 (14.1, 18.6) MRT (h) 16.4 (13.0, 19.7) 21.1 (16.8, 25.5) 23.1 (19.9, 26.4) CL (mL/h/kg) 3.88 (2.91, 4.49) 2.70 (2.30, 3.09) 2.66 (2.34, 2.98) Vss (mL/kg) 58.7 (54.7, 62.6) 49.9 (44.5, 55.3) 60.3 (53.3, 67.3) 1PK parameters are presented in Arithmetic Mean (95% CI) Abbreviations: CI = confidence interval; IR=incremental recovery; AUC = area under the FVIII activity time curve; t½ = elimination half-life; MRT = mean residence time; CL = body weight adjusted clearance; Vss = body weight adjusted volume of distribution at steady-state Carcinogenesis, Mutagenesis, Impairment Of Fertility Long term animal studies investigating the carcinogenic effects of ELOCTATE have not been conducted. Iin vitro and in vivo testing of ELOCTATE for mutagenicity or effects on fertility was not performed. Clinical Studies The safety and efficacy of ELOCTATE was evaluated in a multi-center, prospective, open-label, clinical trial that compared the efficacy of each of two prophylactic treatment regimens (individualized interval and fixed weekly) to episodic (on-demand) treatment; determined hemostatic efficacy in the treatment of bleeding episodes; and determined hemostatic efficacy during perioperative management in subjects undergoing major surgical procedures. The study enrolled a total of 165 previously treated male patients (PTPs) with severe Hemophilia A ( < 1% endogenous Factor VIII activity or a genetic mutation consistent with severe Hemophilia A). Subjects were aged 12 to 65 years, including 13 pediatric subjects aged 12 to 17 years. Of the 165 enrolled subjects, 164 received at least one dose of ELOCTATE and 163 (98%) were evaluable for efficacy. A total of 153 subjects (93%) completed the study. Control and Prevention of Bleeding Episodes A total of 757 bleeding episodes in 106 subjects were treated with ELOCTATE. The majority of the bleeding episodes were spontaneous and localized in joints. The median dose per injection used to treat a bleeding episode was 27.35 (IQR 22.73, 32.71) IU/kg. Assessment of response to each injection was recorded by subjects at 8-12 hours after treatment. Efficacy in control of bleeding episodes is summarized in Table 6. Table 6: Summary of ELOCTATE Efficacy in Control of Bleeding New bleeding episodes (n = 757) # of Injections to treat bleeding episodes 1 injection 661 (87.3%) 2 injections 79 (10.4%) 3 injections 13 (1.7%) ≥ 4 injections 4 (0.5%) Response to first injection* (n = 745) Excellent or good 78.1% Moderate 21.2% No response 0.7% *Excellent: abrupt pain relief and/or improvement in bleeding; Good: definite pain relief and/or improvement in signs of bleeding but possibly requiring more than one injection; Moderate: probable beneficial effect and requiring more than one injection; No response: no improvement or condition worsens. Response evaluated at approximately 8-12 hours after treatment. Perioperative Management Nine major surgical procedures (two laparoscopic, inguinal hernia repairs, five knee surgeries, one appendectomy and one arthroscopy) were performed in nine subjects. The median, pre-operative dose was 51 IU/kg (range 50 – 77). The total dose on the day of surgery ranged from 66 to 115 IU/kg. The hemostatic response for all but one surgery was rated as excellent (blood loss/transfusions less than or similar to a nonhemophilic patient; no extra dose of ELOCTATE needed) and the remaining surgery was rated as good (blood loss no more than 250 mL greater than expected, no extra dose of ELOCTATE needed). An additional 14 minor surgical procedures were performed in 12 subjects. Hemostatic response was available for 12 minor surgeries; it was rated as excellent for 11 and good for 1. Routine Prophylaxis The efficacy of routine prophylaxis (individualized and fixed-weekly regimens) was evaluated against on-demand treatment. A total of 117 subjects received an individualized, twice weekly regimen, which started with 25 IU/kg on the first day followed by 50 IU/kg on the fourth day. The dose and interval were adjusted within the range of 25 – 65 IU/kg every 3-5 days to maintain trough levels between 1% and 3% above baseline, or higher, as clinically indicated to prevent bleeding. The median dosing interval was 3.5 days. Among the 112 subjects treated for at least 6 months, 111 (99%) achieved a dosing interval of three days or longer, 39 (35%) achieved a dosing interval of 4 days or longer, and 33 (29%) achieved a dosing interval of 5 days or longer during the last 3 months on study. Twenty-three subjects received 65 IU/kg of ELOCTATE once weekly for a median period of 28 weeks. An additional 23 subjects received episodic (on-demand) doses of ELOCTATE for the treatment of bleeding episodes and were on study for a median period of 29 weeks. Using a negative binomial model to analyze the annualized bleeding rate (ABR), there was a statistically significant reduction in ABR of 92% (p < 0.001) for subjects in the individualized prophylaxis arm and a statistically significant reduction of 76% (p < 0.001) for subjects in the weekly prophylaxis arm compared to the episodic (on-demand) arm. Fifty-three (53) of 117 (45%) subjects experienced no bleeding episodes while on individualized prophylaxis and 4 of 23 (17%) subjects experienced no bleeding episodes while on weekly prophylaxis. Median ABRs in subjects evaluable for efficacy is summarized in Table 7. Table 7: Median (IQR)1 Annualized Bleed Rate by ELOCTATE Treatment Arm Bleeding Episode Etiology Individualized Prophylaxis (N=117) Weekly Prophylaxis (N=23) Episodic (On-Demand) (N=23) Overall ABR 1.60 (0.0, 4.69) 3.59 (1.86, 8.36) 33.57 (21.14, 48.69) Spontaneous ABR 0.00 (0.0, 2.03) 1.93 (0.0, 4.78) 20.24 (12.21, 36.81) Joint ABR 0.00 (0.00, 3.11) 1.93 (0.00, 7.62) 22.76 (15.07, 39.02) 1 Median (interquartile range, 25th and 75th percentiles) REFERENCES 1. Sommer JM, Moore N, McGuffie-Valentine B, et al. Comparative field study evaluating the activity of recombinant factor VIII Fc fusion protein in plasma samples at clinical haemostasis laboratories. Haemophilia. 2014;20 : 294 – 300.

CLINICAL PHARMACOLOGY Mechanism Of Action Novoeight® temporarily replaces the missing clotting factor VIII that is needed for effective hemostasis. Pharmacodynamics The activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia A. Determination of aPTT is a conventional in vitro assay for the biological activity of FVIII. Treatment with Novoeight® normalizes the aPTT over the effective dosing period. Pharmacokinetics All pharmacokinetic studies with Novoeight® were conducted in previously treated patients with severe hemophilia A (factor VIII ≤ 1%). Analysis of plasma samples was conducted using both the one-stage clotting assay and the chromogenic assay. In a multi-center, multi-national, open-label, single dose pharma­cokinetic study, 23 patients with severe hemophilia A received 50 international units/kg of Novoeight® intravenously. Two patients were below the age of 18 years (13 and 17 years). The pharma­cokinetic parameters for 20 patients who completed the study are summarized in Table 4. Table 4: Pharmacokinetics of Novoeight® in 20 adult and adolescent patients with hemophilia A Parameters Clotting Assay Chromogenic Assay Mean (SD) Mean (SD) Incremental Recovery (IU/mL)/(IU/kg) 0.020 (0.002) 0.028 (0.006) AUC (IU*h/mL) 14.2 (3.8) 18.7 (5.1) CL (mL/h/kg) 3.74 (0.95) 2.87 (0.80) M (h) 10.8 (4.9) 12.0 ( 9.3) Vss (mL/kg) 53.4 (10.9) 44.3 (28.2) Cmax (IU/mL) 1.07 (0.16) 1.54 (0.29) MRT (h) 15.4 (6.4) 16.4 (10.1) In a separate pharmacokinetic study, 28 pediatric patients with severe hemophilia A (14 patients were below 6 years of age and 14 patients were between 6 to < 12 years of age) received a single dose of 50 international units/kg Novoeight®. The pharmacokinetic parameters of Novoeight® are summarized in Table 5 for both age groups. Table 5: Pharmacokinetics of Novoeight® in 28 pediatric patients with hemophilia A Parameters Clotting Assay Chromogenic Assay 0 to < 6 years 6 to < 12 years 0 to < 6 years 6 to < 12 years Mean (SD) Mean (SD) Incremental Recovery (IU/mL)/(IU/kg) 0.018 (0.007) 0.020 (0.004) 0.022 (0.006) 0.025 (0.006) AUC (IU*h/mL) 9.9 (4.1) 11.1 (3.7) 12.2 (4.4) 14.4 (3.5) CL (mL/h/kg) 6.26 (3.73) 5.02 (1.67) 4.60 (1.75) 3.70 (1.00) t½ (h) 7.7 (1.8) 8.0 (1.9) 10.0 (1.7) 9.4 (1.5) Vss (mL/kg) 57.3 (26.8) 46.8 (10.6) 55.8 (23.7) 41.2 (6.0) Cmax (IU/mL) 1.00 (0.58) 1.07 (0.35) 1.12 (0.31) 1.25 (0.27) MRT (h) 9.7 (2.5) 9.9 (2.6) 12.1 (1.9) 11.6 (2.3) The pharmacokinetic parameters were comparable between younger (0 to < 6 years) and older (6 to < 12 years) children. The mean clearance of Novoeight® in younger and older children was 67% and 34% higher (based on per kg body weight) than in adults (3.74 mL/h/ kg) when using the clotting assay, and 60% and 29% higher than in adults (2.87 mL/h/kg) when using the chromogenic assay. The mean half–life of Novoeight® in younger and older children was 29% and 26% shorter than in adults (10.8 hours) when using the clotting assay, and 16% and 21% shorter than in adults (12 hours) when using the chromogenic assay. Clinical Studies Three multi-center, open-label, non-controlled trials have been conducted to evaluate the safety and efficacy of Novoeight® in the control and prevention of breakthrough bleeds, routine prophylaxis and perioperative management in previously treated patients with hemophilia A. The analysis included 213 exposed subjects: 150 adolescents or adult subjects from the age of 12 years ( ≥ 150 exposure days) and 63 pediatric subjects below the age of 12 years ( ≥ 50 exposure days). Immunocompetent patients with severe hemophilia A (factor VIII activity ≤ 1%) and no history of FVIII inhibitors were eligible for the trials. A total of 187 out of 213 subjects continued in the safety extension trial. All subjects received preventive treatment every other day or three times weekly at the dose levels described in Table 3. Breakthrough bleeds were treated at the investigator's discretion aiming for a FVIII activity level above 0.5 IU/mL. Treatment during surgery was at the investigator's discretion aiming for a FVIII trough activity level above 0.5 IU/mL. Control And Prevention Of Bleeding Episodes A total of 991 bleeds in 158 subjects were treated with Novoeight®. The majority of the bleeds (89%) were of mild/moderate severity, 62% of the bleeds were spontaneous and 72% of the bleeds were localized in joints. An overall assessment of efficacy was performed by the subject (for home treatment) or study site investigator (for treatment under medical supervision) using a four-point scale of excellent, good, moderate, or none. If the hemostatic response was rated as “excellent” or “good”, the treatment of the bleed was considered a success. If the hemostatic response was rated as “moderate or none” the treatment was considered a failure. Of these 991 bleeds, 838 (84%) were rated excellent or good in their response to treatment with Novoeight® and 17 (1.7%) were rated as having no response. A total of 898 (91%) of the bleeds were resolved with one or two injections of Novoeight®. Clinical trials of Novoeight® included 79 previously treated patients between one to 16 years of age. The hemostatic efficacy in treatment of bleeds was rated as either “excellent” or “good” on a pre-specified rating scale for 86% of the 244 bleeds reported in 54 subjects. Routine Prophylaxis All 213 subjects received Novoeight® for routine prophylaxis. The prophylactic regimen for the 150 adolescent and adult subjects consisted of 20-40 IU/kg every other day or 20-50 IU/kg three times per week. The prophylactic regimen for the 63 pediatric subjects consisted of 25-50 IU/kg every other day or 25-60 IU/kg three times per week. The majority of the subjects ( > 80%) were treated with the three times per week regimen. The median annualized bleeding rates are provided in Table 6. Table 6: Annualized Bleeding Rate in All Patients Small children 0 - < 6 years Older children 6 - < 12 years Adolescents 12 - < 16 years Adults ≥ 16 years Total Annualized bleeding rate (median) (IQR) 2.9 (6.3) 4.1 (8.6) 4.4 (6.9) 3.1 (5.6) 3.1 (7.3) A total of 68 subjects were treated with Novoeight® for at least 12 months, including seven subjects < 12 years. The ABR was similar for the subjects treated for 12 months when compared to the ABR for the total trial population. Perioperative Management A total of 11 surgeries were performed in 11 previously treated subjects between 14 and 55 years of age, of which 10 were major surgeries (five synovectomies, two total hip arthroplasties, one knee replacement, arthroscopy, and circumcision), and one was minor (tooth extraction). The investigator's ratings of intra- and post-operative quality of hemostasis for these subjects were “excellent” or “good” for all cases.

CLINICAL PHARMACOLOGY Mechanism Of Action KOVALTRY temporarily replaces the missing clotting Factor VIII that is needed for effective hemostasis. Pharmacodynamics Plasma clotting time as measured by the activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia A. Treatment with KOVALTRY normalizes the aPTT. Pharmacokinetics The pharmacokinetics (PK) of KOVALTRY were investigated in PTPs (0 to 61 years of age) with severe Hemophilia A following administration of 50 IU/kg of KOVALTRY. The PK parameters of KOVALTRY are presented in Table 4 (one-stage clotting assay) and Table 5 (chromogenic substrate assay). The PK of KOVALTRY were similar between single and repeat dosing (in 19 subjects following 6 to 12 months of prophylaxis). Table 4: Pharmacokinetic Parameters [Arithmetic Mean ± SD] for KOVALTRY (50 IU/kg dose), One-Stage Clotting Assay Parameter [unit] 12 to 17 yrs (N=5) ≥ 18 yrs (N=21) AUC [IU*h/dL] 1013.9 ± 286.8 1601.3 ± 520.0 Cmax [IU/dL] 91.7 ± 28.7 99.7 ± 14.9 t½ [h] 11.7 ± 1.11 14.3 ± 3.7 MRTiv [h] 16.1 ± 0.8 19.8 ± 5.7 Vss [dL/kg] 0.85 ± 0.24 0.63 ± 0.11 CL [dL/h/kg] 0.053 ± 0.017 0.035 ± 0.012 AUC: area under the curve Cmax: maximum drug concentration in plasma after single dose t½ : terminal half-life MRTIV: mean residence time after an IV administration Vss: apparent volume distribution at steady-state CL: clearance The PK parameters of KOVALTRY for 8 subjects in age group 0 to < 6 years and 10 subjects in age group 6 to < 12 years are shown in Table 5. In general, children < 12 years of age demonstrated lower plasma concentrations when compared to PTP children ≥ 12 years of age. Table 5: Pharmacokinetic Parameters [Arithmetic Mean ± SD] for KOVALTRY (50 IU/kg dose), Chromogenic Substrate Assay Parameter [unit] 0 to < 6 yrs (N=8) 6 to < 12 yrs (N=10)b 12 to 17 yrs (N=5) ≥ 18 yrs (N=21) AUC [IU*h/dL] 1544.7 ± 387.1a 1214.5 ± 395.1 1572.0 ± 448.0 2103.4 ± 702.8 Cmax [IU/dL] 89.6 ± 27.4 81.6± 17.8 132.5 ± 46.3 133.1 ± 20.4 t½ [h] 12.1 ± 2.7a 12.0 ± 2.1 14.4 ± 5.5 14.2 ± 3.5 MRTiv [h] 17.7 ± 3.6a 17.8 ± 2.9 19.8 ± 5.8 19.9 ± 4.9 Vss [dL/kg] 0.57 ± 0.13a 0.79 ± 0.23 0.71 ± 0.39 0.50 ± 0.11 CL [dL/h/kg] 0.033 ± 0.009a 0.045 ± 0.016 0.034 ± 0.010 0.027 ± 0.010 a n=7 b One subject considered PK outlier was excluded Incremental Recovery analysis after 6 months of prophylactic treatment yielded comparable results with incremental recovery after the first dose (see Table 6). Table 6: Incremental Recovery in PTPs 0 to < 6 yrs N=25 2 to 12 yrs N=25 ≥ 12 yrs N=115 Chromogenic substrate assay resultsa Median (Q1; Q3) (IU/dL per IU/kg) 1.6 (1.3; 1.9) 1.7 (1.4; 2.0) 2.3 (1.8; 2.6) One-stage assay resultsa Median (Q1; Q3) (IU/dL per IU/kg) - - 2.2 (1.8; 2.4) aStart of study Clinical Studies The safety and efficacy of KOVALTRY for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis in subjects with severe hemophilia A ( < 1% Factor VIII) was evaluated in three international (including U.S.) clinical studies. Immunocompetent subjects with severe hemophilia A (Factor VIII activity ≤ 1%) and no history of Factor VIII inhibitors were eligible for the trials. Study 1: a multi-center, open-label, cross-over, uncontrolled, study in adolescent and adult (age ≥ 12 years to < 65 years) PTPs ( ≥ 150 EDs) evaluated the pharmacokinetics, efficacy and safety of routine prophylaxis, and perioperative management of bleeding of KOVALTRY (see Table 7). The primary efficacy variable was ABR. The prophylactic regimen was 20 to 50 IU/kg two or three times per week in which the dosing frequency was assigned by the investigator based on the subject's individual requirements. Study 2: a multi-center, open-label, cross-over, uncontrolled, randomized study in adolescent and adult (age ≥ 12 years to < 65 years) PTPs ( ≥ 150 EDs) evaluated the superiority of prophylaxis over on-demand treatment with KOVALTRY over a one-year treatment period (see Table 7). The primary efficacy variable was ABR. The prophylactic regimen was 20 to 30 IU/kg two times per week or 30 to 40 IU/kg three times per week and the treatment group was assigned by randomization. Study 3: a multi-center, open-label, uncontrolled study in pediatric (age ≤ 12 years) PTPs ( ≥ 50 EDs) evaluated the pharmacokinetics, efficacy and safety of routine prophylaxis, and perioperative management of bleeding of KOVALTRY (see Table 8). The primary efficacy variable was annualized number of total bleeds during routine prophylaxis that occurred within 48 hours following previous prophylaxis infusion. ABR during prophylaxis, independent of time of infusion, was also analyzed. The prophylactic regimen was 25 to 50 IU/kg at frequencies of either 2 times per week, 3 times per week or every other day and could be adapted to individual subject's need by the investigator. In all studies, treatments of breakthrough bleeds and perioperative management were at the investigator's discretion based on standard of care. A total of 204 subjects were enrolled in the completed clinical trials, 153 subjects ≥ 12 years of age and 51 subjects < 12 years of age. One hundred-forty (140) subjects were treated for at least 12 months, and 43 of these subjects were treated for 24 months. Table 7: Overview of Study 1 (Prophylaxis Treatment Phase) and Study 2 Study 1 (N=62) Study 2 (N=80) Age: mean ± SD 31.5 ± 12.7 years 29.6 ± 11.0 years Previous treatment: % Prophylaxis: 80.6% On-demand: 100% Number of Target joints at baseline: mean ± SD 1.4 ± 1.3 3.0 ± 2.1 Joint hemorrhage history (during 12 months prior to study): mean ± SD of joint bleeds 8 0 ± 119 32.1 ± 23.8 Table 8: Overview of Study 3 Study 3 PTPs 0 to < 6 yrs (N=25) PTPs 6 to 12 yrs (N=26) Age: mean ± SD (range) 3.8 ± 1.3 years (1-5) 8.8 ± 1.8 years (6-11) Previous treatment: % Prophylaxis: 92.0% Prophylaxis: 65.4% Number of Target joints at baseline: mean ± SD 0.2 ± 0.4 0.7 ± 1.1 On-demand Treatment And Control Of Bleeding Episodes Adolescents And Adults A total of 1892 bleeding episodes in 110 subjects were treated with KOVALTRY in Study 1 and Study 2 (see Table 9). The majority of the bleeding episodes were spontaneous, localized in joints, and mild to moderate in severity. In Study 1 and Study 2, the treatment responses in a total of 1859 treated bleeds were assessed by the subjects compared to their previous treatment experience. Table 9: On-demand Treatment and Control of Bleeding Episodes in Adolescents and Adults Treated with KOVALTRY Characteristics of Bleeding Episodes Study 1 Study 2 Prophylaxis Main Study N=62 Prophylaxis Extension N=55 Prophylaxis N=59 On-demand N=21 Total number of bleeds 241 154 293 1204 Spontaneous: n/total (%) 153/241 (63.5%) 79/150a (52.7%) 209/283a (73.9%) 943/1202a (78.5%) Trauma: n/total (%) 79/241 (32.8%) 70/150a (46.7%) 74/283a (26.1%) 258/1202a (21.5%) Joint bleeds: n/total (%) 191/241 (79.3%) 120/154 (77.9%) 255/293 (87.0%) 924/1197a (77.2%) Mild/moderate: n/total (%) 215/241 (89.2%) 130/153a (84.9%) 260/293 (88.8%) 1092/1196a (91.3%) % of bleeds treated with ≤ 2 infusions 87.0% 96.2% 95.3% Response to treatment of bleeds assessed as “Excellent” or “Good”: n/totalb (%) 190/235 (80.9%) 107/149 (71.8%) 172/279 (61.6%) 834/1196 (69.7%) Median dose per infusion (range) 31.6 IU/kg (14-67 IU/kg) 29.4 IU/kg (19-49 IU/kg) 22.0 IU/kg (11-35 IU/kg) aTotal number excluding uncharacterized bleeds bThe % is calculated from number of treated bleeds assessed for response Children 12 Years Of Age And Younger A total of 97 bleeding episodes in 28 pediatric subjects were treated with KOVALTRY. Majority (96.9%) of the bleeds were mild to moderate in severity. Fifty-nine (72.8%) bleeds were trauma related. During the 6 month treatment period, the median dose of KOVALTRY for the treatment of breakthrough bleeds was 36.94 IU/kg per infusion (range 20.8–71.6 IU/kg). Assessment of response to treatment of bleeds was as follows: Excellent: Abrupt pain relief and/or improvement in signs of bleeding with no additional infusion administered; Good: Definite pain relief and/or improvement in signs of bleeding but possibly requiring more than one infusion for complete resolution; Moderate: Probable or slight improvement in signs of bleeding with at least one additional infusion for complete resolution; Poor: No improvement at all between infusions or condition worsens. The hemostatic efficacy in on-demand treatment of bleeds was assessed as either “good” or “excellent” in 90.1% of cases (97.8% in the younger age group and 81.0% in the older age group). Majority of bleeds (89.7%) were successfully treated with ≤ 2 infusions. Response to treatment was similar for children aged 0 to < 6 compared to 6 to 12 years of age (see Table 10). Table 10: On-demand Treatment and Control of Bleeding Episodes in Children Treated with KOVALTRY Characteristics of Bleeding Episodes Study 3 PTPs 0 to < 6 yrs (N=25) PTPs 2 to 12 yrs (N=22) PTPs 0 to 12 yrs (N=51) Total number of bleeds 52 45 97 Spontaneous: n/total (%) 8/44a (18.2%) 12/37a (32.4%) 20/81a (24.7%) Trauma: n/total (%) 36/44a (81.8%) 23/37a (62.2%) 59/81a (72.8%) Joint bleeds: n/total (%) 10/52 (19.2%) 22/45 (48.9%) 32/97 (33.0%) Mild/moderate: n/total (%) 50/52 (96.2%) 44/45 (97.8%) 94/97 (96.9%) % of bleeds treated with ≤ 2 infusions 92.4% 86.7% 89.7% Response to treatment of bleeds assessed as “Excellent” or “Good”: n/totalb (%) 43/44 (97.8%) 30/37 (81.0%) 73/81 (90.1%) Median dose per infusion (range) 38.7 IU/kg (20.8-71.6 IU/kg) 32.4 IU/kg (21.7-50.0 IU/kg) 36.9 IU/kg (20.8-71.6 IU/kg) aTotal number of treated bleeds bThe % is calculated from number of treated bleeds assessed for response Perioperative Management A total of 14 major and 46 minor surgeries were performed in 44 previously treated subjects (43 adults and adolescents and 1 child under 12 years of age) with severe hemophilia A. Seven of the 14 major surgeries were orthopedic procedures, including joint replacement. Approximately 51% of the minor surgeries were dental extractions. All subjects received KOVALTRY as bolus infusions. In the adolescent and adult subjects, the initial KOVALTRY doses administered ranged between 3000–5000 IU. The median total dose on the day of surgery was 107.5 IU/kg (range 60–207 IU/kg). In a single subject younger than 12 years of age who underwent a major surgery, the total initial KOVALTRY dose administered was 2500 IU (108.7 IU/kg). The blood loss, during and after surgery, was within expected ranges. Hemostatic control was assessed by surgeons as “good” (perioperative bleeding slightly but not clinically significantly increased over expectations for the non-hemophilic patient; treatment similar to non-hemophilic patient) or “excellent” (perioperative blood loss similar to the non-hemophilic patient). Routine Prophylaxis Adolescents And Adults A total of 140 subjects were treated with KOVALTRY for at least 12 months with median (range) 157 EDs (25-178) in Study 1, [305 EDs (25-355) inclusive of extension phase], and 153 EDs (103-187) in Study 2 (see Table 11). In both studies, subjects in the Intent-to-Treat (ITT) population received 95% to 100% of the prescribed number of prophylaxis infusions. Table 11: Prophylaxis Treatment with KOVALTRY in Adolescents and Adults – Treatment Exposure Study 1 (N=62)a Study 2 (N=59) Median nominal prophylaxis dose/ infusion (range) All 31.2 IU/kg (21-43 IU/kg) 31.7 IU/kg (21-42 IU/kg) Prophylaxis 2 times per week 35.0 IU/kg (21-42 IU/kg) 30.4 IU/kg (21-34 IU/kg) Prophylaxis 3 times per week 31.1 IU/kg (24-43 IU/kg) 37.4 IU/kg (30-42 IU/kg) Treatment duration 1 year main study 1 year Study 1: 2 times per week (n=18); 3 times per week (n=44) Study 2: 2 times per week (n=28); 3 times per week (n=31) a Study 1 included PK, safety and efficacy of prophylaxis and hemostasis during surgeries. Prophylaxis phase data are presented. The mean and median ABR for the ITT population in Study 1 was 3.8 ± 5.2 and 1 bleed/year, respectively. In Study 2, comparison of the bleeding rates between subjects receiving on-demand therapy versus prophylaxis in an ANOVA demonstrated a statistically significant difference (p < 0.0001) in the median ABR in subjects receiving on-demand therapy (60 bleeds per year) as compared to subjects receiving prophylaxis (2 bleeds per year). In Study 2, mean ABR in subjects receiving on-demand therapy was 57.7 ± 24.6 versus 4.9 ± 6.8 in the subjects receiving prophylaxis. Table 12: ABR in Adolescent and Adult Subjects Study 1 (N=62) Study 2 (N=59) 2 times per week (n=18) 3 times per week (n=44) 2 times per week (n=28) 3 times per week (n=31) ABR Median (IQRa Q1; Q3) All Bleeds 1.0 (0.0; 8.0) 2.0 (0.5; 5.0) 4.0 (0.0; 8.0) Month 1-6b: 4.1; Month 7-12b: 1.1 2.0 (0.0; 4.9) Month 1-6b: 2.0; Month 7-12b: 2.0 Spontaneous Bleeds 0.5 (0.0; 2.0) 1.0 (0.0; 3.9) 2.0 (0.0; 6.5) 0.0 (0.0; 3.0) Joint Bleeds 0.5 (0.0; 7.0) 1.8 (0.0; 3.0) 2.5 (0.0; 7.5) 1.0 (0.0; 4.0) Subjects with Zero Bleeding Episodesc % (n) 37.5% (6/16d) 62.5% (10/16d) 28.6% (8/28e) 25.8% (8/31e) aIQR = Interquartile Range bMonth 1-6 refers to the first six months of the treatment period and Month 7-12 refer to the second six months of the treatment period cObservation of one-year treatment period dn=total number of subjects with zero bleeds en=total number of subjects randomized to treatment arms The ABR for subjects (n=21) receiving on-demand therapy in Study 2 [median (IQR Q1; Q3)] for all bleeds: 60 (41.7; 76.3); spontaneous bleeds: 42.1 (24.3; 61.3); joint bleeds: 38.8 (24.3; 60.0). Children 12 Years Of Age And Younger A total of 51 PTPs were treated with KOVALTRY for at least 6 months with median (range) 73 EDs (37-103) (see Table 13). Subjects received > 95% of the prescribed number of prophylaxis infusions. Table 13: Prophylaxis Treatment with KOVALTRY in Children 12 Years of Age or Younger – Treatment Exposure Study 3 PTPs 0 to < 6 yrs (N=25) PTPs 2 to 12 yrs (N=22) Treatment regimena during study (6 months) n (%) 2 times per week 9 (36%) 13 (50%) 3 times per week or every other day 16 (64%) 13 (50%) Nominal prophylaxis dose per infusion, median (range) 36.4 IU/kg (21-58 IU/kg) 31.8 IU/kg (22-50 IU/kg) aTreatment regimen at the start of the study. Study duration was six months. In children 12 years of age and younger (n=51), the median (IQR Q1; Q3) ABR within 48 hours after prophylactic infusion was 0 (0; 4) for all bleeds, and 0 (0; 0) for spontaneous and joint bleeds. The median (IQR Q1; Q3) ABR during prophylactic treatment independent of time of infusion was 1.9 (0; 6) for all bleeds, 0 (0; 0) for spontaneous bleeds and 0 (0; 2) for joint bleeds. The mean ABR within 48 hours after prophylactic infusion was 2.04 ± 2.91. The mean ABR at any time during the prophylaxis regimen was 3.75 ± 4.98. In both age groups (0 to < 6 years and 6 to 12 years), the ABR for spontaneous bleeds and joint bleeds within 48 hours after prophylactic treatment [ABR median (IQR Q1; Q3)] was 0 (0; 0). The median (IQR Q1; Q3) annualized number of spontaneous bleeds during prophylactic treatment independent of time of infusion was 0 (0; 0). The median (IQR Q1; Q3) annualized number of joint bleeds during prophylactic treatment independent of time of infusion was 0 (0; 1.9) in 0 to < 6 years age group and 0 (0; 2.1) in 6 to 12 years age group (see Table 14). The majority (32/53) of bleeds that occurred within 48 hours after a previous prophylaxis infusion were trauma related. Twenty-three (45.1%) subjects reported no bleeds during the six-month prophylaxis period. Table 14: ABR in Children 12 Years of Age or Younger Study 3 PTPs 0 to < 6 yrs (N=25) PTPs 2 to 12 yrs (N=22) Within 48 hrs after prophylactic treatment During prophylactic treatmentb Within 48 hrs after prophylactic treatment During prophylactic treatmentb All Bleeds ABR Median (IQRa Q1; Q3) 1.9 (0.0; 4.0) 2.0 (0.0; 6.0) 0.0 (0.0; 2.0) 0.9 (0.0; 5.8) Number of Subjects with Zero Bleeding Episodes (%) 10 (40%) 13 (50%) aIQR = Interquartile Range bIndependent of time of infusion

CLINICAL PHARMACOLOGY AHF is the specific clotting factor deficient in patients with hemophilia A (classical hemophilia). Hemophilia A is a genetic bleeding disorder characterized by hemorrhages which may occur spontaneously or after minor trauma. The administration of RECOMBINATE (antihemophilic factor (recombinant)) rAHF provides an increase in plasma levels of AHF and can temporarily correct the coagulation defect in these patients. Pharmacokinetic studies on sixty-nine (69) patients revealed the circulating mean half- life for rAHF to be 14.6 ± 4.9 hours (n=67), which was not statistically significantly different from plasma-derived HEMOFIL M, Antihemophilic Factor (Human) (AHF) (pdAHF). The mean half- life of HEMOFIL M AHF was 14.7 ± 5.1 hours (n=61). The actual baseline recovery observed with rAHF was 123.9 ± 47.7 IU/dl (n=23) which is significantly higher than the actual HEMOFIL M AHF baseline recovery of 101.7 ± 31.6 IU/dl (n=61). However, the calculated ratio of actual to expected recovery with rAHF (121.2 ± 48.9%) is not different on average from HEMOFIL M AHF (123.4 ± 16.4%). The clinical study of rAHF in previously treated patients (individuals with hemophilia A who had been treated with plasma derived AHF) was based on observations made on a study group of 69 patients. These individuals received cumulative amounts of Factor VIII ranging from 20,914 to 1,383,063 IU over the 48- month study. Patie nts were given a total of 17,700 infusions totaling 28,090,769 IU rAHF. These patients were successfully treated for bleeding episodes on a demand basis and also for the prevention of bleeds (prophylaxis). Spontaneous bleeding episodes successfully managed include hemarthroses, soft tissue and muscle bleeds. Management of hemostasis was also evaluated in surgeries. A total of 24 procedures on 13 patients were performed during this study. These included minor (e.g. tooth extraction) and major (e.g. bilateral osteotomies, thoracotomy and liver transplant) procedures. Hemostasis was maintained perioperatively and postoperatively with individualized AHF replacement. A study of rAHF in previously untreated patients was also performed as part of an ongoing study. The study group was comprised of seventy-nine (79) patients, of whom seventy-six (76) had received at least one infusion of rAHF. To date, this cohort has been given 12,209 infusions totaling over 11,277,043 IU rAHF. Hemostasis was appropriately managed in spontaneous bleeding episodes, intracranial hemorrhage and surgical procedures.

CLINICAL PHARMACOLOGY Mechanism Of Action Kogenate FS temporarily replaces the missing clotting factor VIII that is needed for effective hemostasis. Pharmacodynamics The aPTT is prolonged in patients with hemophilia. Determination of activated partial thromboplastin time (aPTT) is a conventional in vitro assay for biological activity of factor VIII. Treatment with Kogenate FS normalizes the aPTT over the effective dosing period. Pharmacokinetics The pharmacokinetic properties of Kogenate FS were investigated in two separate studies in previously treated patients, adults and children. Pharmacokinetic studies with Kogenate FS were conducted in 20 PTPs (ages 12 to 33 years) with severe hemophilia A in North America. The pharmacokinetic parameters for Kogenate FS were measured in a randomized, crossover clinical trial with the predecessor KOGENATE product with a single dose administration of 50 IU/kg. After 24 weeks, the same dose of Kogenate FS was administered to the same patients. The recovery and half-life data for Kogenate FS were unchanged after 24 weeks of continued treatment with sustained efficacy and no evidence of factor VIII inhibition. [See Table 9.] Table 9 : Pharmacokinetic Parameters for Kogenate FS Compared to KOGENATE Parameter Kogenate FS KOGENATE Initial PK Mean (±SD) PK at week 24 Mean (±SD) Reference Mean (±SD) AUC (IU • h/dL) 1588.05 ± 344.32 1487.08 ± 381.73 1879.02 ± 412.32 Cmax (IU/dL) 114.95 ± 20.19 109.42 ± 20.09 127.40 ± 33.21 Half-life (hr) 13.74 ± 1.82 14.60 ± 4.38 14.07 ± 2.62 In Vivo Recovery (IU/dL / IU/kg) 2.20 ± 0.34 2.11 ± 0.37 2.43 ± 0.60 The pharmacokinetics of Kogenate FS were investigated in pediatric PTPs (4.4-18.1 years of age, average age 12).7 The pharmacokinetic parameters in children compared to adults show differences in higher clearance, lower incremental in vivo factor VIII recovery and a shorter factor VIII half-life. This might be explained by differences in body composition such as body surface area and plasma volume. The pharmacokinetic parameters are depicted in Table 10. Table 10 : Pharmacokinetic Parameters for Kogenate FS in Children Parameter Mean (range) AUC (IU • h/dL) 1320.0 Clearance (mL/h•kg) 4.1 Half-life (hr) 10.7 (7.8-15.3) In Vivo Recovery (IU/dL / IU/kg) 1.9 (1.25-2.76) Clinical Studies Previously Treated Patients A total of 73 patients with severe ( ≤ 2% FVIII) hemophilia A, ages 12–59, who had been previously treated with other recombinant or with plasma-derived AHF products, were treated up to 54-months in open label studies with Kogenate FS in Europe and North America. A total of 5,684 bleeding episodes were treated during the studies. Patients could be treated on demand or on prophylaxis. Regularly scheduled prophylaxis treatment represented 76% of all infusions (treatment regimens of 2-3 infusions per week). [See Table 11.] Table 11 : Previously Treated Patients (PTPs) Clinical Trial Results Clinical Parameters Results No. of Infusions of Kogenate FS Administered 24,924 No. of IU Administered 45 million IU No. of Bleeds Treated with Kogenate FS 5,684 Percentage of Bleeds Treated with One or Two Infusions of Kogenate FS one infusion: 79.7%, two infusions: 13.0% total: 92.7% Mean Kogenate FS Dose per Treatment Infusion (in Europe and North America, Respectively) Approximately 32.5 and 29.6 IU/kg per treatment infusion A total of 30 patients received Kogenate FS for 41 surgical procedures during the PTP studies. There were both minor and major surgery types, 16 and 25 respectively. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories; “excellent”, “good,” “moderate,” or “none.” Hemostasis was rated as satisfactory (“excellent” or “good”) in all cases. [See Table 13.] Previously Untreated And Minimally Treated Patients Kogenate FS has been used in the treatment of bleeding episodes in pediatric previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe ( < 2% FVIII) hemophilia A. There were 37 PUPs and 24 MTPs (defined as having equal to or less than 4 exposure days) treated with a total of 9,419 infusions of Kogenate FS for a follow up duration up to 3.1 years. A total of 1047 bleeding episodes were treated. Table 12 : Previously Untreated and Minimally Treated Patients (PUPs and MTPs) Clinical Trial Results Clinical Parameters Results No. of Infusions of Kogenate FS Administered 9,419 No. of Exposure Days to Kogenate FS (median) 115 exposure days No. of IU Administered 7.5 million IU No. of Bleeds Treated with Kogenate FS 1,047 Percentage of Bleeds Treated with One or Two Infusions of Kogenate FS one infusion 73.1% two infusions 15.0% total: 88.1% A total of 27 surgical procedures were performed in 22 patients during the PUPs and MTPs study. There were both minor and major surgery types, 21 and 6 respectively. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories; “excellent,” “good,” “moderate,” or “none.” Hemostasis was rated as satisfactory (“excellent” or “good”) in all cases. [See Table 13.] Table 13 : Surgical Procedures Performed During PTPs and PUPs/MTPs Clinical Trials Type of Surgery PTPs (N=30) PUPs/MTPs (N=22) No. of Surgical Events Outcome “Good” or “Excellent” No. of Surgical Events Outcome “Good” or “Excellent” Minor Surgery (i.e., tooth extractions, catheter implantations, liver biopsies) 16 100% 21 100% Major Surgery (i.e., joint replacements, craniotomies, gastrointestinal resection) 25 100% 6 100% Total 41 27 Pediatric Prophylaxis And Joint Damage Risk Reduction A total of 65 boys less than 30 months of age with severe hemophilia A (FVIII level ≤ 2 IU/dL) and with ≤ 2 bleeds into each index joint and normal baseline joint imaging, were observed for up to 5.5 years in a multicenter, open-label, prospective, randomized, controlled clinical study.5 Patients received either 25 IU/kg every other day (primary prophylaxis; n=32) or at least 3 doses totaling a minimum of 80 IU/kg at the time of a bleeding episode (enhanced episodic; n=33). Joint damage was evaluated by magnetic resonance imaging (MRI) or radiography, as well as the frequency of bleeding episodes. Joint damage detected by MRI or radiography in the ankles, knees, and elbows (i.e., index joints) was statistically significantly lower (p=0.002) for subjects receiving prophylactic therapy (7%) than for subjects receiving episodic therapy (42%). This corresponds to a 6.29-fold relative risk of joint damage for subjects treated with enhanced episodic therapy compared to prophylaxis. The mean rate of index joint hemorrhages for subjects on episodic therapy was 4.89 bleeds per year, versus 0.63 bleeds per year observed in the prophylaxis arm. Three of 33 (9.1%) subjects in the episodic arm experienced recurrent life threatening bleeds (intracranial, gastrointestinal) compared to no subjects in the prophylaxis arm. On a per joint basis, joints in the regular prophylaxis arm were 8-fold more likely to remain damage-free than those in the episodic arm. Joint damage was most frequently observed in ankle joints and was detected at higher rates by MRI than by radiography. Ankles were also the index joint that demonstrated the highest frequency of bleeding events in this study (left ankle, mean 2.7 hemorrhages; right ankle, mean 2.6 hemorrhages). As shown in Table 14 below, the incidence of joint damage was statistically significantly lower in the prophylactic group as compared to the episodic treatment group when assessed by MRI, or either MRI or radiography, using predefined criteria (described below) for establishing joint damage. However, there was no statistically significant difference between the two groups when joint damage was assessed by radiography alone. To evaluate joint damage, MRIs were scored using a scale developed by Nuss et al.,22 and X-rays were scored using the method of Pettersson et al.23 Both scales have been validated in various clinical trials and are routinely used for joint damage evaluation in hemophiliacs. Joint damage was defined as bone and/or cartilage damage including subchondral cysts, erosions and cartilage loss with narrowing of joint space. This corresponded to a total MRI score of ≥ 7 or an X-ray score of ≥ 1 in any of the following categories: subchondral cysts, erosions of joint surfaces or narrowing of joint spaces. Images were read separately by two independent radiologists centrally. Any discrepant reading was read by an independent third radiologist who was not aware of the initial reading results. The concordant reading of two out of three readers was used for analysis purposes. Table 14 : Subjects with Joint Damage (Subjects with Available Baseline and Endpoint Data) Endpoint Assessment Prophylaxis Episodic Therapy p-value Incidence (%) Relative Risk (95% CI) Incidence (%) Relative Risk (95% CI) MRI 2/27 (7%) 0.17 (0.04, 0.67) 13/29 (45%) 6.05 (1.50, 24.38) 0.002 Radiography 1/28 (4%) 0.19 (0.02, 1.55) 5/27 (19%) 5.19 (0.65, 41.54) 0.101 MRI or Radiography 2/30 (7%) 0.16 (0.04, 0.65) 13/31 (42%) 6.29 (1.55, 25.55) 0.002 Relative Risk is the risk of damage to one or more index joints on the given therapy as compared to the other therapy. P-value is from the 2-sided Fisher Exact Test comparing the incidence of joint damage between treatment groups. As shown in Table 15 below, the assessment of endpoints in all randomized subjects assuming that those without complete baseline and endpoint data are treatment failures (intention-to-treat analysis). The incidence of joint damage was statistically significantly lower in the prophylactic group as compared to the episodic treatment group, with similar pvalues, when assessed by MRI, or either MRI or radiography. Table 15 : Subjects with Joint Damage (All Randomized Subjects Assuming Subjects without Complete Baseline and Endpoint Data as Treatment Failures) Endpoint Assessment Prophylaxis (n=32) Episodic Therapy (n=33) p-value Incidence (%) Relative Risk (95% CI) Incidence (%) Relative Risk (95% CI) MRI 7 (22%) 0.42 (0.20, 0.88) 17 (52%) 2.35 (1.13, 4.90) 0.020 Radiography 5 (16%) 0.47 (0.18, 1.20) 11 (33%) 2.13 (0.83, 5.45) 0.150 MRI or Radiography 8 (25%) 0.43 (0.22, 0.85) 19 (58%) 2.30 (1.18, 4.49) 0.012 Relative Risk is the risk of damage to one or more index joints on the given therapy as compared to the other therapy. P-value is from the 2-sided Fisher Exact Test comparing the incidence of joint damage between treatment groups. REFERENCES 22. Nuss R, Kilcoyne RF, Geraghty S, et al: MRI findings in haemophilic joints treated with radiosynoviorthesis with development of an MRI scale of joint damage. Haemophilia 6:162-169, 2000. 23. Pettersson H, Ahlberg A, Nilsson IM: A radiologic classification of hemophilia arthropathy. Clin Orthop Relat Res 149:153-159, 1980.

CLINICAL PHARMACOLOGY Pharmacokinetic studies were conducted in 20 patients with severe hemophilia A in North America. In this comparative pharmacokinetic study, Helixate FS (antihemophilic factor (recombinant)) was shown to be similar to its predecessor product HELIXATE. Mean FVIII recovery measured 10 minutes following infusion was 2.1 ± 0.3 %/IU/kg for Helixate FS (antihemophilic factor (recombinant)) and 2.4 ± 0.7 %/IU/kg for HELIXATE. The two recoveries were not statistically different (confidence interval 0.815–1.01). The mean biological half-life of recombinant FVIII formulated with sucrose (rFVIII-FS) is similar to HELIXATE with a mean of approximately 13 hours, which has previously been shown to be similar to plasma-derived Antihemophilic Factor (AHF). The activated partial thromboplastin time shortened appropriately with both rFVIII and rFVIII-FS. The recovery and half-life data for rFVIII-FS were unchanged after 24 weeks of exclusive treatment indicating continued efficacy and no evidence of FVIII inhibition. The mean FVIII recovery measured 10 minutes following a dose of rFVIII-FS in 37 patients (after 24 weeks of treatment with rFVIII-FS) was 2.1%/IU/kg, which was unchanged from FVIII recovery determined at baseline and at weeks 4 and 12. Seventy-one patients with severe hemophilia A, ages 12–59, who had been previously treated with other recombinant and with plasma-derived AHF products, were enrolled in 6-month studies of home therapy with rFVIII-FS in Europe and North America. A total of 3995 infusions have been administered under this portion of the study, or 7.4 million units of rFVIII-FS. Treatment of 659 bleeding episodes during the study period required 951 infusions of rFVIII-FS. The majority of bleeding episodes (89.5%) were treated successfully with one or two infusions, using a mean dosage of approximately 28 IU/kg per treatment infusion. Regularly scheduled treatment accounted for 76% of infusions administered on study. Nine patients have received rFVIII-FS on 11 occasions for surgical procedures. The procedures included removal of a brain tumor, two total knee replacements, two joint synovectomies (one with Achilles tendon lengthening), two circumcisions, a hernia repair, and three teeth extractions. Hemostasis was satisfactory in all cases. In clinical studies, Helixate FS (antihemophilic factor (recombinant)) has been used in the treatment of bleeding episodes in previously untreated patients (PUPs) and minimally treated (MTP) pediatric patients. In ongoing studies, 61 PUPs/MTPs have been treated with Helixate FS (antihemophilic factor (recombinant)) . Bleeding episodes were treated effectively with one or two infusions of rFVIII-FS. Ten patients have developed inhibitors. In these trials, approximately half of the patients have achieved 20 or more exposure days, and the incidence of inhibitor formation (15%) is consistent with that observed in other pediatric studies using plasma-derived and recombinant factor VIII products.2-5 REFERENCES 2. Scharrer I, Bray GL, Neutzling O: Incidence of inhibitors in haemophilia A patients — a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Haemophilia 5(3):145-154, 1999. 3. Lusher JM, Arkin S, Abildgaard CF, et al: Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A: safety, efficacy, and development of inhibitors. N Engl J Med 328(7):453-459, 1993. 4. Schwarzinger I, Pabinger I, Korninger C, et al: Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates. Am J Hematol 24(3):241–5, 1987. 5. Ehrenforth S, Kreuz W, Scharrer I, et al: Incidence of development of factor VIII and factor IX inhibitors in hemophiliacs. Lancet 339(8793):594–8, 1992.

CLINICAL PHARMACOLOGY Factor VIII:C is the coagulant portion of the Factor VIII complex circulating in plasma. It is noncovalently associated with the von Willebrand protein responsible for von Willebrand factor activity. These two proteins have distinct biochemical and immunological properties and are under separate genetic control. Factor VIII:C acts as a cofactor for Factor IX to activate Factor X in the intrinsic pathway of blood coagulation.8 Hemophilia A, a hereditary disorder of blood coagulation due to decreased levels of Factor VIII:C, results in profuse bleeding into joints, muscles or internal organs as a result of a trauma. Monoclate-P® provides an increase in plasma levels of AHF, thereby enabling temporary correction of Hemophilia A bleeding. Clinical evaluation of Monoclate-P® concentrate for its half-life characteristics in hemophilic patients showed it to be comparable to other commercially available Antihemophilic Factor (Human) concentrates. The mean half-life obtained from six patients was 17.5 hours with a mean recovery of 1.9 units/dl rise/U/kg. The pasteurization process used in the manufacture of this concentrate has demonstrated in vitro inactivation of human immunodefi ciency virus (HIV) and several model viruses. In two separate studies, HIV was reduced by ≥ 7.0 log10 to an undetectable level and by 10.5 log10, respectively. In addition to HIV, studies were also performed using three lipid containing model viruses and one non-lipid, encapsulated model virus. Vesicular stomatitis (VSV) was reduced by ≥ 6.79 log10 to undetectable, Sindbis was reduced by ≥ 6.48 log10 to undetectable and Vaccinia was reduced by ≥ 5.36 log10 to undetectable. Murine encephalomyocarditis (EMC), a non-lipid, encapsulated model virus, was reduced by ≥ 7.1 log10 to undetectable. Evidence of the capability of the purification and preparative steps used in the production of Monoclate-P® to reduce viral bioburden was obtained in studies involving the addition of known quantities of virus to cryoprecipitate. These studies were conducted using an earlier form of the concentrate which had not undergone liquid pasteurization (Antihemophilic Factor (Human), Monoclate®, Monoclonal Antibody Purified, Factor VIII:C, Heat-Treated). These studies provide evidence of the viral removal potential of the purification and preparative steps of the manufacturing process (exclusive of heat treatment) which are common to both concentrates. In one study, the viruses used were human immunodeficiency virus (HIV), Sindbis virus, vesicular stomatitis virus (VSV) and pseudorabies virus (PsRV). A comparison of the cumulative mean reductions for all viruses tested with the individual values obtained in each experiment indicates that the combined effects of the manufacturing steps, which purify the Factor VIII:C and prepare the concentrate in a fi nal sterile container as a lyophilized powder, contribute viral reduction capabilities of approximately 5 to 6 logs. In a separate study, aluminum hydroxide treatment followed by antibody affi nity chromatography reduced vaccinia virus infectivity by 4.81 logs. These studies indicate that the purifi cation and preparative steps of the manufacturing process are capable of providing a non-specific, viral reduction of approximately 5 to 6 logs, independent of the pasteurization process. Monoclate-P® contains trace amounts of mouse protein9 ( ≤ 50 ng per 100 I.U. of AHF). In a study using an earlier form of the concentrate which had not undergone pasteurization (Monoclate®), a number of patients seronegative for Anti-HIV-1 were monitored to determine whether they would develop antibody or experience adverse reactions as a result of repeated exposure. These patients were treated on multiple occasions. Pre-study serum measurements of 27 patients for human anti-mouse IgG showed that, prior to treatment, 6 of them had either detectable antibody to mouse proteins or cross-reactive proteins. These patients continued to demonstrate similar or lower antibody levels during the study. Of the remaining 21 patients, 6 were shown to have low antibody levels on one or more occasions. In no case was observance of low antibody level associated with an anamnestic response or with any clinical adverse reaction. Patients were observed for time periods ranging from 2 to 30 months. The viral safety of Monoclate-P® has been evaluated in two open-label studies using patients (aged 1 day to 20 years) with moderate to severe hemophilia A previously unexposed to blood or blood products. Thirty patients received Monoclate-P® therapy for 5 to 34 months as necessary according to the normal practices of the treatment center. These patients were followed for serum ALT elevations and a range of viral serologies. Six patients received another blood product prior to or during the study. Twenty-four patients were evaluable for assessment of viral safety of Monoclate-P®. No patients seroconverted to HIV, hepatitis nonA/nonB, or hepatitis B. Factor VIII:C inhibitors developed in 7 patients (23%) with 3 being high ( > 10 BU) titer. REFERENCES 9. F. Feldman, S. Chandra, R. Kleszynski, C.C. Huang and R.L. Weeks, Measurement of Murine Protein Levels in Monoclonal Antibody Purifi ed Coagulation Factor, from the XVIII International Congress of the World Federation of Hemophilia, May 1988.

CLINICAL PHARMACOLOGY Hemophilia A is a hereditary bleeding disorder characterized by deficient coagulant activity of the specific plasma protein clotting factor, factor VIII. In afflicted individuals, hemorrhages may occur spontaneously or after only minor trauma. Surgery on such individuals is not feasible without first correcting the clotting abnormality. The administration of Koate (antihemophilic factor) -DVI provides an increase in plasma levels of factor VIII and can temporarily correct the coagulation defect in these patients. After infusion of Antihemophilic Factor (Human), there is usually an instantaneous rise in the coagulant level followed by an initial rapid decrease in activity, and then a subsequent much slower rate of decrease in activity.2-4 The early rapid phase may represent the time of equilibration with the extravascular compartment, and the second or slow phase of the survival curve presumably is the result of degradation and reflects the true biologic half-life of the infused Antihemophilic Factor (Human).3 The removal and inactivation of spiked relevant and model enveloped and non-enveloped viruses during the manufacturing process for Koate (antihemophilic factor) -DVI have been validated in laboratory studies at Talecris Biotherapeutics, Inc. Studies performed with the model enveloped viruses indicated that the greatest reduction was achieved by TNBP/polysorbate 80 treatment and 80°C heat. For this reason, VSV (Vesicular Stomatitis Virus, model for RNA enveloped viruses) and HIV-1 (Human Immunodeficiency Virus Type 1) were studied only at these two steps of the manufacturing process. The efficacy of the dry heat treatment was studied using all of the viruses, including BVDV (Bovine Viral Diarrheal Virus, model for hepatitis C virus) and Reo (Reovirus Type 3, model for viruses resistant to physical and chemical agents, such as hepatitis A), and the effect of moisture content on the inactivation of HAV (Hepatitis A Virus), PPV (Porcine Parvovirus, model for parvovirus B19), and PRV (Pseudorabies Virus, model for large enveloped DNA viruses) was investigated. Table 1. Summary of In Vitro Log10 Viral Reduction Studies Enveloped Model Viruses Non-enveloped Model Viruses HIV-1 BVDV PRV VSV Reo HAV PPV Model for HIV-1/2 HCV Large enveloped DNA viruses RNA enveloped viruses HAV and viruses resistant to chemical and physical agents HAV B19 Global Reduction Factor ≥ 9.4 ≥ 10.3 ≥ 9.3 ≥ 10.9 9.4 ≥ 4.5 3.7 Similar studies have shown that a terminal 80°C heat incubation for 72 hours inactivates non-lipid enveloped viruses such as hepatitis A and canine parvovirus in vitro, as well as lipid enveloped viruses such as hepatitis C.5, 6, 7 Koate (antihemophilic factor) -DVI is purified by a gel permeation chromatography step serving the dual purpose of reducing the amount of TNBP and polysorbate 80 as well as increasing the purity of the factor VIII. A two-stage clinical study using Koate (antihemophilic factor) -DVI was performed in individuals with hemophilia A who had been previously treated with other plasma-derived AHF concentrates. In Stage 1 of the pharmacokinetic study with 19 individuals, statistical comparisons demonstrated that Koate (antihemophilic factor) -DVI is bioequivalent to the unheated product, Koate (antihemophilic factor) w-HP. The incremental in vivo recovery ten minutes after infusion of Koate (antihemophilic factor) -DVI was 1.90% IU/kg (Koate (antihemophilic factor) -HP 1.82% IU/kg). Mean biologic half-life of Koate (antihemophilic factor) -DVI was 16.12 hours (Koate (antihemophilic factor) -HP 16.13 hours). In Stage II of the study, participants received Koate (antihemophilic factor) -DVI treatments for six months on home therapy with a median of 54 days (range 24–93). No evidence of inhibitor formation was observed, either in the clinical study or in the preclinical investigations.2 REFERENCES 2. Data on file. 3. Aronson DL: Factor VIII (antihemophilic globulin). Semin Thromb Hemostas 6(1):12–27, 1979. 4. Britton M, Harrison J, Abildgaard CF: Early treatment of hemophilic hemarthroses with minimal dose of new factor VIII concentrate. J Pediatr 85(2):245–7, 1974. 5. Winkelman L., Feldman PA, Evan DR: Severe heat treatment of lyophilised coagulation factors in Virus Inactivation in Plasma Products. Curr Stud Hematol Blood Transfus. Morgenthaler J-J (ed.), Basel, Karger, 1989, No. 56, pp. 55-69. 6. Skidmore SJ, Pasi KJ, Mawson SJ, et al: Serological evidence that dry heating of clotting factor concentrates prevents transmission of non-A, non-B hepatitis. J. Med Virol. 30(1):50-2, 1990. 7. Hart HF, Hart WG, Crossley J, et al: Effect of terminal (dry) heat treatment on non-enveloped viruses in coagulation factor concentrates. Vox Sang 67(4): 345-50, 1994.

CLINICAL PHARMACOLOGY AHF is the specific clotting factor deficient in patients with hemophilia A (classical hemophilia). Hemophilia A is a genetic bleeding disorder characterized by hemorrhages which may occur spontaneously or after minor trauma. The administration of Bioclate (antihemophilic factor) † provides an increase in plasma levels of AHF and can temporarily correct the coagulation defect in these patients. Pharmacokinetic studies on sixty-six (66) patients revealed the circulating mean half-life for rAHF to be 14.4 ±4.9 hours, which was not statistically significantly different from plasma-derived Antihemophilic Factor (Human), HemofilÒM, (pdAHF), which had a mean half-life of 14.0 ±3.9 hours (n = 59). Mean highest in vivo recovery in plasma was also similar at 2.18 ±0.72 (n = 19) IU/dL per IU/kg body weight compared to the mean highest recovery point above the pre-infusion baseline for HemofilÒM of 1.97 ±0.66 (n = 57) IU/dL per IU/kg. The clinical study of rAHF in previously treated patients (individuals with hemophilia A who had been treated with plasma derived AHF) was based on observations made on a study group of 67 patients. These individuals received 18,451 to 1,110,111 IU over the 58.2 month study period in 13,394 infusions for a total of 21,437,195 IU rAHF. These patients were successfully treated for bleeding episodes on a demand basis and also for the prevention of bleeds (prophylaxis). Spontaneous bleeding episodes successfully managed include hemarthroses, soft tissue and muscle bleeds. Management of hemostasis was also evaluated in surgeries. A total of 24 procedures on 13 patients were performed during this study. These included minor (e.g. tooth extraction) and major (e.g. bilateral osteotomies, thoracotomy and liver transplant) procedures. Hemostasis was maintained perioperatively and postoperatively with individualized AHF replacement. A study of rAHF in previously untreated patients was also performed. The study group comprised seventy-nine (79) patients of whom seventy-five (75) had received at least one infusion of rAHF. In total this cohort has been given 1,054 infusions totalling 437,126 IU rAHF. Hemostasis was appropriately managed in spontaneous bleeding episodes, intracranial hemorrhage and surgical procedures.

CLINICAL PHARMACOLOGY Mechanism Of Action ALPHANATE contains antihemophilic factor (FVIII) and von Willebrand factor (VWF), constituents of normal plasma. FVIII is an essential cofactor in activation of factor X leading to formation of thrombin and fibrin. VWF promotes platelet aggregation and platelet adhesion on damaged vascular endothelium; it also serves as a stabilizing carrier protein for the procoagulant protein FVIII.12, 13 After administration, ALPHANATE temporarily replaces the missing coagulation factor VIII and von Willebrand factor needed for effective hemostasis. Pharmacokinetics Pharmacokinetics In Hemophilia A Following the administration of ALPHANATE during clinical trials, the mean in vivo half-life of FVIII observed in 12 adult subjects with severe hemophilia A was 17.9 ± 9.6 hours. In this same study, the in vivo recovery was 96.7 ± 14.5% at 10 minutes postinfusion. Recovery at 10 minutes post-infusion was also determined as 2.4 ± 0.4 IU FVIII rise/dL plasma per IU FVIII infused/kg body weight. Pharmacokinetics In Von Willebrand Disease (VWD) A pharmacokinetic crossover study was conducted in 14 non-bleeding subjects with VWD (1 type 1, 2 type 2A, and 11 type 3) comparing the pharmacokinetics of ALPHANATE (A-SD/HT) and an earlier formulation, ALPHANATE (A-SD). Subjects received, in random order at least seven days apart, a single intravenous dose of each product, 60 IU VWF:RCo/kg (75 IU VWF:RCo/kg in subjects younger than 18 years of age). Pharmacokinetic parameters were similar for the two products and indicated that they were biochemically equivalent. Pharmacokinetic analysis of ALPHANATE (A-SD/HT) in the 14 subjects revealed the following results: the median plasma levels (% normal) of VWF:RCo rose from 10 IU/dL (range: 10 to 27 IU/dL) at baseline to 206 IU/ dL (range: 87 to 440 IU/dL) 15 minutes post-infusion; median plasma levels of FVIII:C rose from 5 IU/dL (range: 2 to 114 IU/dL) to 206 IU/dL (range: 110 to 421 IU/dL). The median bleeding time (BT) prior to infusion was 30 minutes (mean, 28.8 ± 4.41 minutes; range: 13.5 to 30 minutes), which shortened to 10.38 minutes (mean, 10.4 ± 3.2 minutes; range: 6 to 16 minutes) 1 hour post-infusion. Following infusion of ALPHANATE (A-SD/HT), the median half-lives for VWF:RCo, FVIII:C and VWF:Ag were 6.91 hours (range: 3.8 to 16.22 hours), 20.92 hours (range: 7.19 to 32.2 hours), and 12.8 hours (range: 10.34 to 17.45 hours), respectively. The median incremental in vivo recoveries of VWF:RCo and FVIII:C were 3.12 (IU/dL)/(IU/kg) [range: 1.28 to 5.73 (IU/dL)/(IU/kg)] for VWF:RCo and 1.95 (IU/dL)/(IU/kg) [range: 1.33 to 3.32 (IU/dL)/(IU/kg)] for FVIII:C. The pharmacokinetic data in VWD are summarized in Table 4. Table 4: Pharmacokinetic data in VWD Parameter Plasma VWF:RCo (Mean ± SD) Plasma FVIII:C (Mean ± SD) Plasma VWF:Ag (Mean ± SD) Number of subjects 14 14 14 Mean plasma levels (IU/dL) Baseline 11.86 ± 4.97 21.00 ± 33.83 - 15 minutes post infusion 215.50 ± 101.70 215.29 ± 94.26 - T½ (Half-life in hours) 7.67 ± 3.32 21.58 ± 7.79 13.06 ± 2.20 Incremental in vivo recovery in (IU/dL)/(IU/kg) 3.29 ± 1.46 2.13 ± 0.58 - Following infusion of both ALPHANATE (A-SD) and ALPHANATE (A-SD/HT), an increase in the size of VWF multimers was seen and persisted for at least 24 hours. The shortening of the BT was transient, lasting less than 6 hours following treatment and did not correlate with the presence of large and intermediate size VWF multimers.14 Clinical Studies In a prospective, multi-center clinical study, 37 subjects with VWD (6 Type 1, 19 Type 2, 12 Type 3) underwent 59 surgical procedures for which ALPHANATE (A-SD) or ALPHANATE (A-SD/HT) was administered [21 subjects received ALPHANATE (A-SD), 18 received ALPHANATE (A-SD/HT), and 2 received both products] for bleeding prophylaxis (see Table 5). An initial pre-operative infusion of 60 IU VWF:RCo/kg (75 IU VWF:RCo/kg for subjects less than 18 years of age), was administered one hour before surgery. A blood sample was obtained 15 minutes after the initial infusion for the determination of the plasma FVIII:C level. The level had to equal or exceed 100% of normal for an operation to proceed. No cryoprecipitate or alternative FVIII product was administered during these surgical procedures. Platelets were required in two subjects. The protocol permitted intraoperative infusions of ALPHANATE (A-SD) and ALPHANATE (A-SD/HT) at 60 IU VWF:RCo/kg (75 IU VWF:RCo/kg for subjects less than 18 years of age) to be administered as required according to the judgment of the investigator. Table 5: Number of and Types of Surgical Procedures Parameter Treatment with ALPHANATE Total Type of Surgical Procedure A-SD A-SD/HT Number of Subjects 21 18 37^ Dental 14 6 20 Dermatologic 1 1 2 Gastrointestinal 4 4 8 Gastrointestinal (diagnostic) 6 0 6 Genitourinary 0 2 2 Gynecologic 2 1 3 Head and neck 1 1 2 Orthopedic 4 3 7 Vascular 3 6 9 Total number of procedures 35 24 59 ^ Two subjects received both preparations; the total number of subjects is therefore less than the sum of the columns. Post-operative infusions at doses of 40 to 60 IU VWF:RCo/kg (50 to 75 IU VWF:RCo/kg for pediatric subjects) were administered at 8 to 12-hour intervals until healing had occurred. For maintenance of secondary hemostasis (after primary hemostasis was achieved), the dose was reduced after the third post-operative day. [see DOSAGE AND ADMINISTRATION]. Overall, in the surgical procedures using either product, the BT at 30 minutes post-infusion was fully corrected in 18 (32.7%) cases, partially corrected in 24 (43.6%) cases, not corrected in 12 (21.8%) cases, and was not done in one case (1.8%). Overall, the mean blood loss was lower than predicted prospectively. Surgical infusion summary data are included in Table 6. Table 6: Prophylaxis with ALPHANATE (A-SD) and/or ALPHANATE (A-SD/HT) in Surgery Parameter A-SD A-SD/HT Total Number of subjects 21 18 37* Number of surgical procedures 35 24 59 Median number of infusions per surgical procedure (range) 3 (1-13) 4 (1-18) 4 (1-18) Median dosage IU VWF:RCo/kg Infusion #1 (range) 59.8 (19.8-75.1) 59.9 (40.6-75.0) 59.9 (19.8-75.1) Infusion ≥ #2 combined (range) 40.0 (4.5-75.1) 40.0 (10.0-63.1) 40.0 (4.5-75.1) * Two subjects received both products. Additionally, surgical procedures using ALPHANATE SD/HT only were categorized as major, minor or invasive procedures according to definitions used in the study. The outcome of each surgery was evaluated according to a clinical rating scale (excellent, good, poor or none) and was considered successful if the outcome was excellent or good. Study results also were evaluated independently by two referees with clinical experience in this field in the same way (surgery categorization and outcome of each surgery according to a clinical rating scale). There was a high level of agreement between the referee evaluations and the analyzed outcome data, with a decrease of only a single success in achieving hemostasis (21/24 [referees evaluation] vs. 22/24 [investigators evaluation]). A retrospective, multi-center study was performed to assess the efficacy of ALPHANATE (A-SD/ HT) as replacement therapy in preventing excessive bleeding in subjects with congenital VWD undergoing surgical or invasive procedures, for whom DDAVP was ineffective or inadequate. A total of 61 surgeries/procedures in 39 subjects were evaluated.15 Of the 39 subjects, 18 had Type 1 VWD (46.2%); 12 subjects (30.8%) had Type 2 VWD, and 9 subjects (23.1%) had Type 3 VWD. Median age was 40 years; approximately one-half of the subjects were male. The primary efficacy variable was the overall treatment outcome for each surgical or invasive procedure, as rated by the investigator using a 4-point verbal rating scale (VRS): “excellent,” “good,” “poor,” or “none (no indication of efficacy).” The categorization of the replacement treatment outcome was based upon the investigator's clinical experience and defined in Table 7. Table 7: Rating Scale and Clinical Efficacy of ALPHANATE Therapy Rating Clinical Efficacy* Hemostasis Dosing Excellent Hemostasis not different from that expected for subjects without known bleeding disorders. No upward dosage adjustment for ALPHANATE replacement therapy. Good Hemostasis slightly inferior from that expected for subjects without known bleeding disorders but judged as not clinically relevant. Minor upward dosage adjustment for ALPHANATE replacement therapy. Poor Less hemostasis than expected for subjects without known bleeding disorders attributed to vWD despite ALPHANATE replacement therapy. Relevant upward dosage adjustment for ALPHANATE replacement therapy. No need for alternative therapy. None Severe bleeding attributed to vWD despite ALPHANATE replacement therapy. Relevant upward dosage adjustment for ALPHANATE replacement therapy and/or need for alternative unexpected therapy. * The efficacy assessment period included the entire perioperative period. In addition, an independent referee committee was convened to evaluate the efficacy outcomes. More than 90% of the surgical outcomes received an investigator and referee's overall and daily rating of “effective” (“excellent” or “good”) in achieving hemostasis/preventing bleeding. The majority of ratings were considered “excellent” ( ≥ 81.3% in each VWD type). Nine Type 3 subjects underwent 1 major and 15 minor procedures. Two procedures (1 major and 1 minor) in 1 subject with Type 3 VWD received an overall efficacy rating of “none,” and one minor procedure in a subject with Type 2 VWD received an overall efficacy rating of “poor.” REFERENCES 12. Hoyer, L.W. The Factor VIII Complex: Structure and Function. Blood 1981; 58:1-13. 13. Meyer, D., Girma, J-P. von Willebrand Factor: Structure and Function. Thrombosis and Haemostasis 1993; 70:99-104. 14. Mannucci, P.M., Chediak, J., Hanna, W. Byrnes, J.J., Kessler, C.M., Ledford, M., Retzios, A.D., Kapelan, B.A., Gallagher, P., Schwartz, R.S., and the Alphanate Study Group. Treatment of von Willebrand's Disease (VWD) with a high purity factor VIII concentrate: Dissociation between correction of the bleeding time (BT), VWF multimer pattern, and treatment efficacy. Blood 1999; 94 (Suppl 1, Part 2 of 2):98b. 15. Rivard, G.E., Aledort, L., et al. Efficacy of factor VIII/von Willebrand factor concentrate Alphanate in preventing excessive bleeding during surgery in subjects with von Willebrand disease. Haemophilia 2008; 14, 271-275.

Find Lowest Prices on XYNTHA (antihemophilic factor [recombinant]) for Intravenous Use, Freeze-Dried Powder DESCRIPTION The active ingredient in XYNTHA, Antihemophilic Factor (Recombinant), is a recombinant antihemophilic factor (rAHF), also called coagulation factor VIII, which is produced by recombinant DNA technology. It is secreted by a genetically engineered Chinese hamster ovary (CHO) cell line. The cell line is grown in a chemically defined cell culture medium that contains recombinant insulin, but does not contain any materials derived from human or animal credits. The rAHF in XYNTHA is a purified glycoprotein, with an approximate molecular mass of 170 kDa consisting of 1,438 amino acids, which does not contain the B-domain.13 The amino acid sequence of the rAHF is comparable to the 90 + 80 kDa form of human coagulation factor VIII. The purification process uses a series of chromatography steps, one of which is based on affinity chromatography using a patented synthetic peptide affinity ligand.14 The process also includes a solvent-detergent viral inactivation step and a virus-retaining nanofiltration step. The potency expressed in International Units (IU) is determined using the chromogenic assay of the European Pharmacopoeia. The Wyeth manufacturing reference standard for potency has been calibrated against the World Health Organization (WHO) International Standard for factor VIII activity using the one-stage clotting assay. The specific activity of XYNTHA is 5,500 to 9,900 IU per milligram of protein. XYNTHA is formulated as a sterile, nonpyrogenic, no preservative, lyophilized powder preparation for intravenous injection. Each singleuse vial contains nominally 250, 500, 1000, or 2000 IU of XYNTHA. Upon reconstitution, the product is a clear to slightly opalescent, colorless solution that contains sodium chloride, sucrose, L-histidine, calcium chloride, and polysorbate 80. REFERENCES 13. Sandberg H, Almstedt A, Brandt J, Castro VM, Gray E, Holmquist L, et al. Structural and Functional Characterization of B-Domain Deleted Recombinant Factor VIII. Sem Hematol. 2001;38 (Suppl. 4):4–12. 14. Kelley BD, Tannatt M, Magnusson R, Hagelberg S. Development and Validation of an Affinity Chromatography Step Using a Peptide Ligand for cGMP Production of Factor VIII. Biotechnol Bioeng. 2004;87(3):400–412.

ReFacto® Antihemophilic Factor, Recombinant DESCRIPTION ReFacto® Antihemophilic Factor (Recombinant) is a purified protein produced by recombinant DNA technology for use in therapy of factor VIII deficiency. ReFacto (antihemophilic factor) is a glycoprotein with an approximate molecular mass of 170 kDa consisting of 1438 amino acids. It has an amino acid sequence that is comparable to the 90 + 80 kDa form of factor VIII, and post-translational modifications that are similar to those of the plasma-derived molecule. ReFacto (antihemophilic factor) has in vitro functional characteristics comparable to those of endogenous factor VIII. ReFacto (antihemophilic factor) is produced by a genetically engineered Chinese hamster ovary (CHO) cell line. The CHO cell line secretes B-domain deleted recombinant factor VIII into a defined cell culture medium that contains human serum albumin and recombinant insulin, but does not contain any proteins derived from animal sources. The protein is purified by a chromatography purification process that yields a high-purity, active product. The potency expressed in international units (IU) is determined using the European Pharmacopoeial chromogenic assay against the WHO standard. The specific activity of ReFacto (antihemophilic factor) is 9110-13700 IU per milligram of protein. ReFacto (antihemophilic factor) is not purified from human blood and contains no preservatives or added human or animal components in the final formulation. ReFacto (antihemophilic factor) is formulated as a sterile, nonpyrogenic, lyophilized powder preparation for intravenous (IV) injection. It is available in single-use vials containing the labeled amount of factor VIII activity (IU). Each vial contains nominally 250, 500, 1000 or 2000 IU of ReFacto (antihemophilic factor) per vial. The formulated product is a clear colorless solution upon reconstitution and contains sodium chloride, sucrose, L-histidine, calcium chloride, and polysorbate 80.

Find Lowest Prices on OBIZUR [Antihemophilic Factor (Recombinant), Porcine Sequence] Powder for Intravenous Injection DESCRIPTION The active ingredient in OBIZUR is a recombinant (r) analogue of porcine factor VIII (pFVIII) with an approximate molecular weight of 170 kDa. The rpFVIII molecule in OBIZUR is a glycoprotein containing a 90 kDa heavy chain and a 80 kDa light chain. The B-domain normally present in naturally occurring porcine factor VIII has been replaced with a twenty-four amino acid linker. Once activated, the resulting rpFVIIIa has a comparable activity to the endogenous human FVIIIa. OBIZUR is expressed in a genetically engineered baby hamster kidney (BHK) cell line which secretes rpFVIII into the cell culture medium, and the rpFVIII protein is purified using a series of chromatography and filtration steps. The production process includes two dedicated viral clearance steps - a solvent/detergent treatment step for viral inactivation and a nanofiltration step through a series of two 15-nm filters for removal of viruses. No additives of human or animal origin are used in the formulation of OBIZUR. OBIZUR is formulated as a sterile, non-pyrogenic, lyophilized powder for intravenous injection after reconstitution with the diluent (Sterile Water for Injections). OBIZUR is available in single-use vials that nominally contain 500 units (U) per vial. When reconstituted with the diluent, the product contains the following components per mL: 8.8 mg sodium chloride, 0.04 mg Tris-base, 0.73 mg Tris-HCl, 1.47 mg tri-sodium citrate dehydrate, 0.15 mg calcium chloride dehydrate, 1.9 mg sucrose, and 0.05 mg polysorbate 80. Each vial of OBIZUR is labeled with the actual rpFVIII activity expressed in units determined by a one-stage clotting assay, using a reference rpFVIII material calibrated against the World Health Organization (WHO) 8th International Standard for human FVIII concentrates. The specific activity of OBIZUR is in the range of 11000 - 18000 U per milligram of protein. The potency values of OBIZUR determined by the chromogenic assay vary and are approximately 20-50 % lower than those of the one-stage clotting assay.

Find Lowest Prices on ADYNOVATE [Antihemophilic Factor (Recombinant), PEGylated] Lyophilized Powder for Reconstitution for Intravenous Injection DESCRIPTION ADYNOVATE, Antihemophilic Factor (Recombinant), PEGylated, is formulated as a sterile, non-pyrogenic, white to off-white lyophilized powder for reconstitution for intravenous injection. The product is supplied in single-use vials containing nominal (approximate) potencies of 250, 500, 1000, or 2000 international units (IU). Each vial of ADYNOVATE is labeled with the actual factor VIII activity in IU determined using one-stage clotting assay, using a reference material calibrated against a World Health Organization (WHO) International Standard for factor VIII concentrates. One IU, as defined by the WHO standard for blood coagulation factor VIII, human, is approximately equal to the level of factor VIII activity found in 1 mL of fresh pooled human plasma. When reconstituted with 5 mL sterile water for injection, the final solution contains the following excipients and stabilizer in targeted amounts per vial: Stabilizer and Excipient 5 mL Reconstitution Target Tris (hydroxymethyl) aminomethane 6.1 mg Calcium Chloride 1.2 mg Mannitol 160 mg Sodium Chloride 26.3 mg Trehalose Dihydrate 40 mg Glutathione .04 mg Histidine 7.8 mg Polysorbate 80 0.5 mg ADYNOVATE contains no preservative. The specific activity of ADYNOVATE is 2700 - 8000 IU/mg protein. ADYNOVATE is a recombinant full-length human coagulation factor VIII (2,332 amino acids with a molecular weight (MW) of 280 kDa) covalently conjugated with one or more molecules of polyethylene glycol (MW 20 kDa). [see CLINICAL PHARMACOLOGY]. The therapeutic activity of ADYNOVATE is derived from its parent drug substance, ADVATE [Antihemophilic Factor (Recombinant)], which is produced by recombinant DNA technology from the CHO cell line. ADVATE is purified from the culture medium using a series of chromatography columns. The purification process includes an immunoaffinity chromatography step in which a monoclonal antibody directed against factor VIII is employed to selectively isolate the factor VIII from the medium. The production process includes a dedicated, viral inactivation solvent-detergent treatment step. The ADVATE molecule is then covalently conjugated with the polyethylene glycol, which mainly targets lysine residues. The cell culture, pegylation, purification process and formulation used in the manufacture of ADYNOVATE do not use additives of human or animal origins.

Find Lowest Prices on ELOCTATE™ [Antihemophilic Factor (Recombinant), Fc Fusion Protein] for Intravenous Injection DESCRIPTION ELOCTATE, Antihemophilic Factor (Recombinant), Fc Fusion Protein, is a sterile, non-pyrogenic, lyophilized powder for reconstitution for intravenous injection. The product is supplied in single use vials containing nominal potencies of 250, 500, 750, 1000, 1500, 2000 or 3000 international units (IU). Each vial of ELOCTATE is labeled with the actual content in IU. The powder for injection is reconstituted with 3 mL sterile water for injection (SWFI) supplied in a sterile prefilled syringe. The reconstituted product contains the excipients: sucrose, sodium chloride, L-histidine, calcium chloride and polysorbate 20. ELOCTATE contains no preservatives. B-domain deleted recombinant Factor VIII, Fc fusion protein (BDD-rFVIIIFc) is the active ingredient in ELOCTATE. BDD-rFVIIIFc is a recombinant protein consisting of a B-domain deleted analogue of human Coagulation Factor VIII covalently linked to the human immunoglobulin G1 (IgG1) Fc domain sequence. The Factor VIII portion of the molecule has a 90 kDa heavy chain and an 80 kDa light chain (similar to endogenous Factor VIII), which are linked by 14 (of 908) amino acids from the central B-domain. The FVIII portion has post-translational modifications comparable to endogenous Factor VIII. The Fc domain of the molecule contains the hinge, CH2, and CH3 regions of IgG1. BDD-rFVIIIFc contains 1890 amino acids with an apparent molecular weight of 220 kDa. The majority of the expressed protein is proteolytically processed to a two chain molecule; however ELOCTATE may also contain up to 39% of a single chain, non-processed form. Both molecules have been shown to have comparable Factor VIII activity. BDD-rFVIIIFc is produced by recombinant DNA technology from a human embryonic kidney (HEK) cell line, which has been extensively characterized. The HEK cell line expresses BDD-rFVIIIFc into a defined, cell culture medium that does not contain any proteins derived from animal or human sources. BDD-rFVIIIFc is purified using a series of chromatography steps, including affinity capture with a recombinant, single chain antibody fragment produced in a yeast expression system. No human or animal derived proteins are used in the purification or formulation processes. The production process also incorporates two dedicated viral clearance steps - a detergent treatment step for inactivation and a 15 nm filtration step for removal of viruses.

Find Lowest Prices on Novoeight®, Antihemophilic Factor (Recombinant) Lyophilized Powder for Intravenous Injection DESCRIPTION Novoeight® is formulated as a sterile, non-pyrogenic, lyophilized powder for intravenous injection after reconstitution with the diluent (0.9% sodium chloride). Novoeight® is available in single-dose vials that contain nominally 250, 500, 1000, 1500, 2000 or 3000 international units (IU) per vial. When reconstituted with the appropriate volume of diluent, the product contains the following components per mL: 18 mg sodium chloride, 1.5 mg L-histidine, 3 mg sucrose, 0.1 mg polysorbate 80, 0.055 mg L-methionine and 0.25 mg calcium chloride dihydrate. The product contains no preservative. Each vial of Novoeight® is labeled with the actual rFVIII activity expressed in IU determined by the one-stage clotting assay, using a reference material calibrated against a World Health Organization (WHO) International Standard for FVIII Concentrates. One IU, as defined by the WHO standard for human FVIII, is approximately equal to the level of FVIII activity in 1 mL of fresh pooled human plasma. The specific activity of Novoeight® is approximately 8340 IU per milligram of protein. The active ingredient in Novoeight® is a recombinant (r) analogue of human coagulation factor VIII (FVIII) with a molecular mass of 166 kDa, calculated excluding post-translational modifications. The rFVIII molecule in Novoeight® is a glycoprotein containing a heavy chain and a light chain, with 21 of the 908 amino acids of the B-domain of endogenous FVIII connected to the C-terminus of the heavy chain. Once activated, the resulting rFVIIIa has a comparable structure to the endogenous FVIIIa. Novoeight® is synthesized by a genetically engineered Chinese hamster ovary (CHO) cell line which secretes rFVIII into the cell culture medium. The rFVIII protein is purified using a series of chromatography steps, one of which is the use of an immunoaffinity column in which a monoclonal antibody, produced in CHO cells and directed against FVIII, is employed to selectively isolate the rFVIII from the medium. The production process includes two dedicated viral clearance steps - a detergent treatment step for inactivation and a 20-nm filtration step for removal of viruses. No additives of human or animal origin are used in the cell culture, purification and formulation of Novoeight®.

Find Lowest Prices on KOVALTRY [Antihemophilic Factor (Recombinant)] for Intravenous Administration DESCRIPTION KOVALTRY, Antihemophilic Factor (Recombinant), is a sterile, non-pyrogenic, white to slightly yellow powder for reconstitution contained in a single-use vial. The final product does not contain any preservative. The reconstituted product is indicated for intravenous administration. The product is available in 250 IU, 500 IU, 1000 IU, 2000 IU, or 3000 IU nominal potencies; however, for each dosage strength the actual, assayed Factor VIII potency is directly printed on each vial label. The container closure system consists of a 10 mL, Type I glass vial sealed with a bromobutyl grey stopper and an aluminum crimp seal with plastic flip-off cap plus vial adapter. The vial adapter was designed to connect with the sterile water for injection (sWFI), prefilled diluent syringe. KOVALTRY is formulated with the following excipients: 2.2% glycine, 1% sucrose, 30 mM sodium chloride, 2.5 mM calcium chloride, 20 mM histidine and 80 ppm polysorbate 80. The pH of the reconstituted product is 6.6 to 7.0. Intravenous administration of sucrose contained in KOVALTRY will not affect blood glucose level. The active substance in KOVALTRY is the unmodified full length recombinant Factor VIII glycoprotein comprising the human derived amino acid sequence. Post-translational modifications are similar to those of endogenous Factor VIII including glycosylation sites and sulfation of tyrosine sites. Manufacturing and quality controls ensure that both galactose-alpha-1,3-galactose (alpha-Gal) and N-glycolyl neuraminic acid (NGNA) content are below the 1% limit of detection established for each analytical method. KOVALTRY is produced by a genetically engineered Baby Hamster Kidney (BHK) cell line into which the human Factor VIII gene was introduced together with the human heat shock protein 70 (HSP 70) gene. HSP 70 is an intracellular protein that improves proper folding of the Factor VIII protein. While KOVALTRY and Kogenate FS have the same protein backbone, human- and animal-derived raw materials are not added to the cell culture, purification, or formulation processes for KOVALTRY. In the manufacturing process for KOVALTRY, recombinant Factor VIII is secreted into cell culture medium and is purified from process- and product-related impurities using a series of chromatography and filtration steps. The production process incorporates two dedicated viral clearance steps: (1) a detergent treatment step for inactivation and (2) a 20 nanometer filtration step for removal of viruses and potential protein aggregates.

Find Lowest Prices on RECOMBINATE Antihemophilic Factor (Recombinant) for Injection DESCRIPTION RECOMBINATE, Antihemophilic Factor (Recombinant) (rAHF) is a glycoprotein synthesized by a genetically engineered Chinese Hamster Ovary (CHO) cell line. In culture, the CHO cell line secretes recombinant antihemophilic factor (rAHF) into the cell culture medium. The rAHF is purified from the culture medium utilizing a series of chromatography columns. A key step in the purification process is an immunoaffinity chromatography methodology in which a purification matrix, prepared by immobilization of a monoclonal antibody directed to factor VIII, is utilized to selectively isolate the rAHF in the medium. The synthesized rAHF produced by the CHO cells has the same biological effects as Antihemophilic Factor (Human) [AHF (Human)]. Structurally the protein has a similar combination of heterogenous heavy and light chains as found in AHF (Human). RECOMBINATE (antihemophilic factor recombinant) rAHF is formulated as a sterile, nonpyrogenic, off- white to faint yellow, lyophilized powder preparation of concentrated recombinant AHF for intravenous injection. RECOMBINATE (antihemophilic factor recombinant) rAHF is available in single-dose bottles which contain nominally 250, 500 and 1000 International Units per bottle. When reconstituted with the appropriate volume of diluent, the product contains the following stabilizers in maximum amounts: 12.5 mg/mL Albumin (Human), 0.20 mg/mL calcium, 1.5 mg/mL polyethylene glycol (3350), 180 mEq/L sodium, 55 mM histidine, 1.5 µg/AHF international Unit (IU) polysorbate-80. Von Willebrand Factor (vWF) is coexpressed with the Antihemophilic Factor (Recombinant) and helps to stabilize it. The final product contains not more than 2 ng vWF/IU rAHF which will not have any clinically relevant effect in patients with von Willebrand's disease. The product contains no preservative. Manufacturing of RECOMBINATE (antihemophilic factor recombinant) rAHF is shared by Baxter Healthcare Corporation and Wyeth BioPharma. The recombinant Antihemophilic Factor Concentrate (For Further Manufacturing Use), is produced by Baxter Healthcare Corporation and Wyeth BioPharma (For Further Manufacturing Use) and subsequently formulated and packaged at Baxter Healthcare Corporation. Each bottle of RECOMBINATE (antihemophilic factor recombinant) rAHF is labeled with the AHF activity expressed in IU per bottle. Biological potency is determined by an in vitroassay which is referenced to the World Health Organization (WHO) International Standard for Factor VIII:C Concentrate.

Find Lowest Prices on KOGENATE FS [Antihemophilic Factor (Recombinant), Formulated with Sucrose] DESCRIPTION Kogenate FS Antihemophilic Factor (Recombinant) is a coagulation factor VIII produced by recombinant DNA technology. It is produced by Baby Hamster Kidney (BHK) cells into which the human factor VIII gene has been introduced.8 The cell culture medium contains Human Plasma Protein Solution (HPPS) and recombinant insulin, but does not contain any proteins derived from animal sources. Kogenate FS is a purified glycoprotein consisting of multiple peptides including an 80 kD and various extensions of the 90 kD subunit. It has the same biological activity as factor VIII derived from human plasma. No human or animal proteins, such as albumin, are added during the purification and formulation processes of Kogenate FS. The purification process includes a solvent/detergent virus inactivation step in addition to the use of the purification methods of ion exchange chromatography, monoclonal antibody immunoaffinity chromatography, along with other chromatographic steps designed to purify recombinant factor VIII and remove contaminating substances. Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.9-21 Several of the individual production and raw material preparation steps in the Kogenate FS manufacturing process have been shown to decrease TSE infectivity of that experimental model agent. TSE reduction steps include the Fraction II+III separation step for HPPS (6.0 log10) and an anion exchange chromatography step (3.6 log10). Kogenate FS is formulated with the following as stabilizers [see Table 7] in the final container and is then lyophilized. The final product is a sterile, nonpyrogenic, preservative-free, powder preparation for intravenous (IV) injection. Intravenous administration of sucrose contained in Kogenate FS will not affect blood glucose levels. Table 7 : Stabilizers Contained in Kogenate FS Final Container Stabilizer 250 IU, 500 IU, 1000IU 2000 IU, 3000 IU Sucrose 0.9- 1.3% 0.9-1.2% Glycine 21-25 mg/mL 20-24 mg/mL Histidine 18-23 mmol/L 17-22 mmol/L The following inactive ingredients/excipients are also contained in the final product: Table 8 : Inactive Ingredients/Excipients Inactive Ingredient/Excipient 250 IU, 500 IU, 1000 IU 2000 IU, 3000 IU Sodium 27-36 mEq/L 26-34 mEq/L Calcium 2.0-3.0 mmol/L 1.9-2.9 mmol/L Chloride 32-40 mEq/L 31-38 mEq/L Polysorbate 80 64-96 μg/mL 64-96 μg/mL Sucrose 28 mg/vial 52 mg/vial Imidazole, tri-n-butyl phosphate, and copper Trace amounts Trace amounts Each vial of Kogenate FS contains the labeled amount of recombinant factor VIII in international units (IU). One IU, as defined by the World Health Organization standard for blood coagulation factor VIII, human, is approximately equal to the level of factor VIII activity found in 1 mL of fresh pooled human plasma. REFERENCES 8. Lawn RM, Vehar GA: The molecular genetics of hemophilia. Sci Am 254(3):48–54, 1986. 9. Kimberlin RH, Walker CA: Characteristics of a short incubation model of scrapie in the golden hamster. J Gen Virol 34(2):295-304, 1977. 10. Kimberlin RH, Walker CA: Evidence that the transmission of one source of scrapie agent to hamsters involves separation of agent strains from a mixture. J Gen Virol 39(3):487-96, 1978. 11. Kimberlin RH, Walker CA: Pathogenesis of scrapie (strain 263K) in hamsters infected intracerebrally, intraperitoneally or intraocularly. J Gen Virol 67(2):255-63, 1986. 12. Prusiner SB, et al: Further purification and characterization of scrapie prions. Biochemistry 21(26):6942-50, 1982. 13. Kascsak RJ, et al: Mouse polyclonal and monoclonal antibody to scrapie-associated fibril proteins. J Virol 61(12):3688-93, 1987. 14. Rubenstein R, et al: Scrapie-infected spleens: analysis of infectivity, scrapie-associated fibrils, and protease-resistant proteins. J Infect Dis 164(1):29-35, 1991. 15. Taylor DM, Fernie K: Exposure to autoclaving or sodium hydroxide extends the dose-response curve of the 263K strain of scrapie agent in hamsters. J Gen Virol 77(4):811-13, 1996. 16. Stenland CJ, et al: Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma. Transfusion 42(11):1497-500, 2002. 17. Lee DC, Miller JL, Petteway SR: Pathogen safety of manufacturing processes for biological products: special emphasis on KOGENATE® Bayer. Haemophilia 8(Suppl. 2):6-9, 2002. 18. Lee DC, Stenland CJ, Hartwell, RC, et al: Monitoring plasma processing steps with a sensitive Western blot assay for the detection of the prion protein. J Virol Methods 84(1):77-89, 2000. 19. Lee DC, Stenland CJ, Miller JL, et al: A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins. Transfusion 41(4):449-55, 2001. 20. Cai K, Miller JL, Stenland CJ, et al: Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 1597(1):28-35, 2002. 21. Trejo SR, Hotta JA, Lebing W, et al: Evaluation of virus and prion reduction in a new intravenous immunoglobulin manufacturing process. Vox Sang 84(3):176-87, 2003.

Find Lowest Prices on Helixate® FS Antihemophilic Factor (Recombinant) Formulated with Sucrose DESCRIPTION Helixate® FS Antihemophilic Factor (recombinant) is a sterile, stable, purified, nonpyrogenic, dried concentrate that has been manufactured using recombinant DNA technology. Helixate FS (antihemophilic factor recombinant) is intended for use in the treatment of classical hemophilia (hemophilia A), and is produced by Baby Hamster Kidney (BHK) cells into which the human factor VIII (FVIII) gene has been introduced.1 The cell culture medium contains Human Plasma Protein Solution (HPPS) and recombinant insulin, but does not contain any proteins derived from animal sources. Helixate FS is a highly purified glycoprotein consisting of multiple peptides including an 80 kD and various extensions of the 90 kD subunit. It has the same biological activity as FVIII derived from human plasma. Compared to its predecessor product HELIXATE® Antihemophilic Factor (Recombinant), Helixate FS (antihemophilic factor recombinant) incorporates a revised purification and formulation process that eliminates the addition of Albumin (Human). The purification process includes an effective solvent/detergent virus inactivation step in addition to the use of the classical purification methods of ion exchange chromatography, monoclonal antibody immunoaffinity chromatography, along with other chromatographic steps designed to purify recombinant FVIII and remove contaminating substances. Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.15-27 Several of the individual production and raw material preparation steps in the Helixate FS (antihemophilic factor recombinant) manufacturing process have been shown to decrease TSE infectivity of that experimental model agent. TSE reduction steps included the Fraction II+III separation step for Human Plasma Protein Solution (6.0 log10) and an anion exchange chromatography step (3.6 log10). These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed. Helixate FS (antihemophilic factor recombinant) is formulated with sucrose (0.9–1.3%), glycine (21–25 mg/mL), and histidine (18–23 mM) as stabilizers in the final container in place of Albumin (Human) as used in HELIXATE, and is then lyophilized. The final product also contains calcium chloride (2–3 mM), sodium (27–36 mEq/L), chloride (32–40 mEq/L), polysorbate 80 (64-96 µg/mL), and trace amounts of imidazole, tri-n-butyl phosphate, and copper. The product contains no preservatives. The amount of sucrose in each vial is 28 mg.(250, 500, and 1000 IU sizes) and 56mg. Intravenous administration of sucrose contained in Helixate FS (antihemophilic factor recombinant) will not affect blood glucose levels. Each vial of Helixate FS contains the labeled amount of recombinant FVIII in international units (IU). One IU, as defined by the World Health Organization standard for blood coagulation FVIII, human, is approximately equal to the level of FVIII activity found in 1 mL of fresh pooled human plasma. Helixate FS (antihemophilic factor recombinant) must be administered by the intravenous route. REFERENCES 1. Lawn RM, Vehar GA: The molecular genetics of hemophilia. Sci Am 254(3):48–54, 1986. 15. Kimberlin RH, Walker CA: Characteristics of a short incubation model of scrapie in the golden hamster. J Gen Virol 34(2):295-304, 1977. 16. Kimberlin RH, Walker CA: Evidence that the transmission of one source of scrapie agent to hamsters involves separation of agent strains from a mixture. J Gen Virol 39(3):487-96, 1978. 17. Kimberlin RH, Walker CA: Pathogenesis of scrapie (strain 263K) in hamsters infected intracerebrally, intraperitoneally or intraocularly. J Gen Virol 67(2):255-63, 1986. 18. Prusiner SB, et al: Further purification and characterization of scrapie prions. Biochemistry 21(26):6942-50, 1982. 19. Kascsak RJ, et al: Mouse polyclonal and monoclonal antibody to scrapie-associated fibril proteins. J Virol 61(12):3688-93, 1987. 20. Rubenstein R, et al: Scrapie-infected spleens: analysis of infectivity, scrapie-associated fibrils, and protease- resistant proteins. J Infect Dis 164(1):29-35, 1991. 21. Taylor DM, Fernie K: Exposure to autoclaving or sodium hydroxide extends the dose-response curve of the 263K strain of scrapie agent in hamsters. J Gen Virol 77(4):811-13, 1996. 22. Stenland CJ, et al: Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma. Transfusion 42(11):1497-500, 2002. 23. Lee DC, Miller JL, Petteway SR: Pathogen safety of manufacturing processes for biological products: special emphasis on KOGENATE® Bayer. Haemophilia 8(Suppl. 2):6-9, 2002. 24. Lee DC, Stenland CJ, Hartwell RC, et al: Monitoring plasma processing steps with a sensitive Western blot assay for the detection of the prion protein. J Virol Methods 84(1):77-89, 2000. 25. Lee DC, Stenland CJ, Miller JL, et al: A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins. Transfusion 41(4):449-55, 2001. 26. Cai K, Miller JL, Stenland CJ, et al: Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 1597(1):28-35, 2002. 27. Trejo SR, Hotta JA, Lebing W, et al: Evaluation of virus and prion reduction in a new intravenous immunoglobulin manufacturing process. Vox Sang 84(3):176-87, 2003.

Find Lowest Prices on Antihemophilic Factor (Human) Monoclate-P® Factor VIII:C Pasteurized Monoclonal Antibody Purified DESCRIPTION Antihemophilic Factor (Human), Monoclate-P®, Factor VIII:C Pasteurized, Monoclonal Antibody Purified, is a sterile, stable, lyophilized concentrate of Factor VIII:C with reduced amounts of VWF:Ag and purified of extraneous plasma-derived protein by use of affinity chromatography. A murine monoclonal antibody to VWF:Ag is used as an affinity ligand to first isolate the Factor VIII Complex. Factor VIII:C is then dissociated from VWF:Ag, recovered, formulated and provided as a sterile lyophilized powder.1,2,3 The concentrate as formulated contains Albumin (Human) as a stabilizer, resulting in a concentrate with a specific activity between 4 and 10 units/mg of total protein. In the absence of this added Albumin (Human) stabilizer, specific activity has been determined to exceed 3000 units/mg of protein.4 Monoclate-P® has been prepared from pooled human plasma and is intended for use in therapy of classical hemophilia (Hemophilia A). All Source Plasma used in the manufacture of this product was tested by FDA-licensed Nucleic Acid Testing (NAT) for HBV, HCV, and HIV-1 and found to be nonreactive (negative). This concentrate has been pasteurized by heating at 60°C for 10 hours in aqueous solution form during its manufacture in order to further reduce the risk of viral transmission.5 However, no procedure has been shown to be totally effective in removing viral infectivity from coagulant factor concentrates (see CLINICAL PHARMACOLOGY and WARNINGS). Monoclate-P® is a highly purifi ed preparation of Factor VIII:C. When stored as directed, it will maintain its labeled potency for the period indicated on the container and package labels.6,7 Upon reconstitution of the 250, 500 and 1000 I.U. concentrates, a clear, colorless solution is obtained, containing 50 to 150 times as much Factor VIII:C as does an equal volume of plasma. Upon reconstitution of the 1500 I.U. concentrate, a clear, colorless solution is obtained, containing 120 to 180 times as much Factor VIII:C as does an equal volume of plasma. Each vial contains the labeled amount of antihemophilic factor (AHF) activity as expressed in terms of International Units (I.U.) of antihemophilic activity. One unit of antihemophilic activity is equivalent to that quantity of AHF present in one mL of normal human plasma. When reconstituted as recommended, the resulting solution contains approximately 300 to 450 millimoles of sodium ions per liter and has 2 to 3 times the tonicity of saline. It contains approximately 2-5 millimoles of calcium ions per liter, contributed as calcium chloride, approximately 1 to 2% Albumin (Human), 0.8% mannitol, and 1.2 mM histidine. The pH is adjusted with hydrochloric acid and/or sodium hydroxide. Monoclate-P® also contains trace amounts ( ≤ 50 ng per 100 I.U. of AHF) of the murine monoclonal antibody used in its purification (see CLINICAL PHARMACOLOGY). Monoclate-P® is to be administered only intravenously. REFERENCES 1. W. Terry, A. Schreiber, C. Tarr, M. Hrinda, W. Curry and F. Feldman, Human Factor VIII:C Produced Using Monoclonal Antibodies, in Research in Clinic and Laboratory, Vol. XVI, (#1), 202 (1986) from the XVIIth International Congress of the World Federation of Hemophilia. 2. A. B. Schreiber, The Preclinical Characterization of Monoclate Factor VIII C Antihemophilic Factor Human, Semin Hematol 25 (2 Suppl. 1), 1988, pp. 27-32. 3. E. Berntorp and I.M. Nilsson, Biochemical Properties of Human Factor VIII C Monoclate Purified Using Monoclonal Antibody to VWF, Thromb Res O (Suppl. 7), 1987, p. 60, from the Satellite Symposia of the XIth International Congress on Thrombosis and Haemostasis, Brussels, Belgium, July 11, 1987. 4. S. Chandra, C.C. Huang, R.L. Weeks, K. Beatty and F. Feldman, Purity of a Factor VIII:C Preparation (Monoclate) Manufactured by Monoclonal Immunoaffi nity Chromatography Technique, from the XVIII International Congress of the World Federation of Hemophilia, May 1988. 5. B. Spire, D. Dormont, F. Barre-Sinousii, L. Montagnier, and J.C. Chermann, Inactivation of Lymphadenopathy Associated Virus by Heat, Gamma Rays, and Ultraviolet Light, Lancet, Jan. 26, 1985, p. 188. 6. F. Feldman, R. Kleszynski, L. Ho, R. Kling, S. Chandra and C.C. Huang, Validation of Coagulation Test Methods for Evaluation of Monoclate (Factor VIII:C) Potencies, from the XVIII International Congress of the World Federation of Hemophilia, May 1988. 7. S. Chandra, C.C. Huang, L. Ho, R. Kling, R.L. Weeks and F. Feldman, Studies on the Stability of Factor VIII:C (Monoclate) in Lyophilized and Solution Form, from the XVIII International Congress of the World Federation of Hemophilia, May 1988.

Koate® -DVI Antihemophilic Factor (Human) Double Viral Inactivation Solvent/Detergent Treated and Heated in Final Container at 80°C DESCRIPTION Antihemophilic Factor (Human), Koatew-DVI, is a sterile, stable, purified, dried concentrate of human Antihemophilic Factor (AHF, factor VIII, AHG) which has been treated with tri-n-butyl phosphate (TNBP) and polysorbate 80 and heated in lyophilized form in the final container at 80°C for 72 hours. Koate (antihemophilic factor) -DVI is intended for use in therapy of classical hemophilia (hemophilia A). Koate (antihemophilic factor) -DVI is purified from the cold insoluble fraction of pooled fresh-frozen plasma by modification and refinements of the methods first described by Hershgold, Pool, and Pappenhagen.1 Koate (antihemophilic factor) -DVI contains purified and concentrated factor VIII. The factor VIII is 300–1000 times purified over whole plasma. Part of the fractionation may be performed by another licensed manufacturer. When reconstituted as directed, Koate (antihemophilic factor) -DVI contains approximately 50–150 times as much factor VIII as an equal volume of fresh plasma. The specific activity, after addition of Albumin (Human), is in the range of 9–22 IU/mg protein. Koate (antihemophilic factor) -DVI must be administered by the intravenous route. Each bottle of Koate-DVI contains the labeled amount of antihemophilic factor activity in international units (IU). One IU, as defined by the World Health Organization standard for blood coagulation factor VIII, human, is approximately equal to the level of AHF found in 1.0 mL of fresh pooled human plasma. The final product when reconstituted as directed contains not more than (NMT) 1500 μg/mL polyethylene glycol (PEG), NMT 0.05 M glycine, NMT 25μg/mL polysorbate 80, NMT 5μg/g tri-n-butyl phosphate (TNBP), NMT 3 mM calcium, NMT 1μg/mL aluminum, NMT 0.06 M histidine, and NMT 10 mg/mL Albumin (Human). REFERENCES 1. Hershgold EJ, Pool JG, Pappenhagen AR: The potent antihemophilic globulin concentrate derived from a cold insoluble fraction of human plasma: characterization and further data on preparation and clinical trial. J Lab Clin Med 67(1):23–32, 1966.

BIOCLATE™ (antihemophilic factor [recombinant]) DESCRIPTION Antihemophilic Factor (Recombinant), Bioclate (antihemophilic factor) TM is a glyco-protein synthesized by a genetically engineered Chinese Hamster Ovary (CHO) cell line. In culture the CHO cell line secretes recombinant antihemophilic factor (rAHF) into the cell culture medium. The rAHF is purified from the culture medium utilizing a series of chromatography columns. A key step in the purification process is an immunoaffinity chromatography methodology in which a purification matrix prepared by immobilization of a monoclonal antibody directed to factor VIII is utilized to selectively isolate the rAHF in the medium. The rAHF produced has the same biological effects as Antihemophilic Factor (Human) [AHF(Human)] and structurally has a similar combination of heterogeneous heavy and light chains as found in AHF (Human). Bioclate (antihemophilic factor) TM is formulated as a sterile, nonpyrogenic, off-white to faint yellow, lyophilized powder preparation of concentrated recombinant AHF for intravenous injection and is available in single-dose bottles which contain nominally 250, 500 and 1000 International Units per bottle. When reconstituted with the appropriate volume of diluent, it contains the following stabilizers in maximum amounts: 12.5 mg/mL Albumin (Human), 1.5 mg/mL polyethylene glycol (3350),180 mEq/L sodium, 55 mM histidine, 1.5 pg/AHF International Unit (IU) polysorbate-80 and 0.20 mg/mL calcium. Von Willebrand Factor (vWF) is coexpressed with the Antihemophilic Factor (Recombinant) and helps to stabilize it. The final product contains not more than 2 ng vWF/IU rAHF which will not have any clinically relevant effect in patients with von Willebrands disease. The product contains no preservative. Manufacturing of Bioclate (antihemophilic factor) TM is shared by Baxter Healthcare Corporation, Hyland Division and Genetics Institute, Inc. Genetics Institute produces Antihemophilic Factor Concentrate (Recombinant) (For Further Manufacturing Use) which is then formulated and packaged at Baxter Healthcare Corporation, Hyland Division. Each bottle of Bioclate (antihemophilic factor) TM is labeled with the AHF activity expressed in IU per bottle. Biological potency is determined by an in vitro assay which is referenced to the World Health Organization (WHO) International Standard for Factor VIII:C Concentrate.

Find Lowest Prices on Alphanate® (Antihemophilic Factor/von Willebrand Factor Complex [Human]) Lyophilized Powder for Solution for Intravenous Injection DESCRIPTION ALPHANATE, (antihemophilic factor/von Willebrand factor complex [human]), is a sterile, lyophilized concentrate of FVIII (AHF) and von Willebrand Factor (VWF). ALPHANATE is prepared from pooled human plasma by cryoprecipitation of FVIII, fractional solubilization, and further purification employing heparin-coupled, cross-linked agarose which has an affinity to the heparin binding domain of VWF/FVIII:C complex. The product is treated with a mixture of tri-n-butyl phosphate (TNBP) and polysorbate 80 to inactivate enveloped viruses. The product is also subjected to an 80 °C heat treatment step for 72 hours to inactivate enveloped and non-enveloped viruses. However, no procedure has been shown to be totally effective in removing viral infectivity from coagulation factor products. ALPHANATE is labeled with the antihemophilic factor potency (FVIII:C activity) in International Units (IU) FVIII/vial and with VWF:RCo activity expressed in IU VWF:RCo/vial. The activities are referenced to their respective international standards established by the World Health Organization. One IU of FVIII or one IU of VWF:RCo is approximately equal to the amount of FVIII or VWF:RCo activity in 1 mL of freshly-pooled human plasma. ALPHANATE contains human albumin as a stabilizer, resulting in a final container concentrate with a specific activity of at least 5 FVIII:C IU/mg total protein. ALPHANATE contains no preservatives. The composition of ALPHANATE after reconstitution is as follows: Name of Ingredients Nominal Composition Units/ Container Factor VIII von Willebrand Factor 250 > 400 500 > 400 1000> 400 1500> 400 2000 > 400 I.U. I.U. per 1000 I.U. Factor VIII Albumin (Human) 25 25 50 50 50 mg Arginine 90 90 175 175 175 mg Histidine 20 20 40 40 40 mg Water for Injectiona 5 5 10 10 10 mL aSupplied in a separate diluent vial Viral Reduction Capacity The results of virus validation studies performed to determine virus reduction factors associated with several steps in the manufacturing process of ALPHANATE are summarized in Table 3. In vitro inactivation studies to evaluate the solvent detergent treatment (0.3% Tri-n-butyl Phosphate and 1.0% Polysorbate 80) step in the manufacture of ALPHANATE were conducted to assess the capability of the step to inactivate enveloped viruses, such as Human Immunodeficiency viruses (HIV), as well as marker viruses such as Sindbis virus (SIN, a model for Hepatitis C virus), Vesicular Stomatitis virus (VSV, a model for large, enveloped RNA virus), Bovine Herpes virus (BHV, a model for Hepatitis B virus) and Bovine Viral Diarrhea virus (BVD, a model for Hepatitis C virus). In vitro inactivation studies to evaluate the dry heat treatment (80 °C, 72 hours) step in the manufacture of ALPHANATE were conducted to assess the capability of the step to inactivate both enveloped and non-enveloped viruses, such as Hepatitis A virus (HAV), human Poliovirus Sabin type 2 (POL, a model for HAV), Canine Parvovirus (CPV, a model for Parvovirus B19), BHV and BVD. Other steps in the manufacturing process of ALPHANATE (precipitation with 3.5% polyethylene glycol (PEG), heparin affinity chromatography and lyophilization) were also evaluated for virus elimination capability using several enveloped and non-enveloped viruses as shown in Table 3. Table 3: Virus Log Reduction Virus (Model Virus for) 3.5% PEG Precipitation Solvent- Detergent Column Chromatography Lyophilization Dry Heat Cycle (80°C, 72 h) Total Log Reduction BHV (HBV) < 1.0 ≥ 8.0 7.6 1.3 2.1 ≥ 19.0 BVD (HCV) < 1.0 ≥ 4.5 < 1.0 < 1.0 ≥ 4.9 ≥ 9.4 POL (HAV) 3.3 - < 1.0 3.4 ≥ 2.5 ≥ 9.2 CPV (B19) 1.2 - < 1.0 < 1.0 4.1 5.3 VSV - ≥ 4.1 - - - ≥ 4.1 SIN (HCV) - ≥ 4.7 - - - ≥ 4.7 HIV-1 < 1.0 ≥ 11.1 > 2.0 - - ≥ 13.1 HIV-2 - ≥ 6.1 - - - ≥ 6.1 HAV - - - 2.1 > 5.8 ≥ 7.9 Additionally, the manufacturing process was investigated for its capacity to decrease infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents. Several of the individual production steps in ALPHANATE manufacturing process have been shown to decrease TSE infectivity of an experimental model agent.11 TSE reduction steps include: 3.5% polyethylene glycol precipitation (3.23 log10), affinity chromatography (3.50 log10) and saline precipitation (1.36 log10). These studies provide reasonable assurance that low levels of CJD/Vcjd agent infectivity, if present in the starting material, would be removed. REFERENCES 11. Diez JM, Caballero S, Belda P, Otegui M, Gajardo R, Jorquera JI. Elimination capacity of a TSE-model agent in the manufacturing process of Alphanate/Fanhdi, a human factor VIII/VWF complex concentrate. Haemophilia. 2009. 15(6):1249-1257.

INDICATIONS XYNTHA, Antihemophilic Factor (Recombinant), is indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for: Control and prevention of bleeding episodes Perioperative management XYNTHA does not contain von Willebrand factor, and therefore is not indicated in patients with von Willebrand's disease. DOSAGE AND ADMINISTRATION For intravenous use after reconstitution only. Dose Initiate treatment with XYNTHA under the supervision of a physician experienced in the treatment of hemophilia A. Dosage and duration of treatment depend on the severity of the factor VIII deficiency, the location and extent of bleeding, and the patient's clinical condition. Titrate the administered doses to the patient's clinical response. One International Unit (IU) of factor VIII activity corresponds approximately to the quantity of factor VIII in one milliliter of normal human plasma. The calculation of the required dosage of factor VIII is based upon the empirical finding that, on average, 1 IU of factor VIII per kg body weight raises the plasma factor VIII activity by approximately 2 IU/dL.2 The expected in vivo peak increase in factor VIII level expressed as IU/dL (or % normal) can be estimated using the following formulas: Dosage (International Units) = body weight (kg) × desired factor VIII rise (IU/dL or % of normal) × 0.5 (IU/kg per IU/dL) or IU/dL (or % normal) = Total Dose (IU)/body weight (kg) × 2 [IU/dL]/[IU/kg] Control And Prevention Of Bleeding Episodes A guide for dosing XYNTHA for the control and prevention of bleeding episodes is provided in Table 1. Maintain the plasma factor VIII activity at or above the levels (in % of normal or in IU/dL) outlined in Table 1 for the indicated period. Table 1: Dosing for Control and Prevention of Bleeding Episodes Type of Bleeding Episode Factor VIII Level Required (IU/dL or % of normal) Frequency of Doses (hours) Duration of Therapy Minor Early hemarthrosis, minor muscle or oral bleeds. 20-40 12-24 At least 1 day, depending upon the severity of the bleeding episode. Moderate Bleeding into muscles. Mild head trauma. Bleeding into the oral cavity. 30-60 12-24 3-4 days or until adequate local hemostasis is achieved. Major Gastrointestinal bleeding. Intracranial, intraabdominal, or intrathoracic bleeding. Fractures. 60-100 8-24 Until bleeding is resolved. Perioperative Management A guide for dosing XYNTHA during surgery (perioperative management) is provided in Table 2. Maintain the plasma factor VIII activity level at or above the level (in % of normal or in IU/dL) outlined in Table 2 for the indicated period. Monitor the replacement therapy by means of plasma factor VIII activity. Table 2: Dosing for Perioperative Management Type of Surgery Factor VIII Level Required (IU/dL or % of normal) Frequency of Doses (hours) Duration of Therapy (days) Minor Minor operations, including tooth extraction. 30-60 12-24 3-4 days or until adequate local hemostasis is achieved. For tooth extraction, a single infusion plus oral antifibrinolytic therapy within 1 hour may be sufficient. Major Major operations. 60-100 8-24 Until threat is resolved, or in the case of surgery, until adequate local hemostasis and wound healing are achieved. Preparation And Reconstitution Preparation Always wash hands before performing the following procedures. Use aseptic technique during the reconstitution procedures. Use all components in the reconstitution and administration of this product as soon as possible after opening their sterile containers to minimize unnecessary exposure to the atmosphere. Note: If the patient uses more than one vial of XYNTHA per infusion, reconstitute each vial according to the following instructions. Remove the diluent syringe, leaving the vial adapter in place. Use a separate 10 milliliter or larger luer lock syringe (not included in this kit) to draw back the reconstituted contents of each vial. Do not detach the diluent syringe or the large luer lock syringe until ready to attach the large luer lock syringe to the next vial adapter. If the patient uses one vial of XYNTHA with one XYNTHA SOLOFUSE™ for the infusion, reconstitute the vial and the syringe according to the instructions for each respective product kit. Use a separate 10 milliliter or larger luer lock syringe (not included in this kit) to draw back the reconstituted contents of the vial and the syringe. [see Use of a XYNTHA Vial Kit with a XYNTHA SOLOFUSE™ Kit] Reconstitution 1. Allow the XYNTHA vial and the prefilled diluent syringe to reach room temperature. 2. Remove the plastic flip-top cap from the XYNTHA vial to expose the central portions of the rubber stopper. 3. Wipe the top of the vial with the alcohol swab provided, or use another antiseptic solution, and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any surface. 4. Peel back the cover from the clear plastic vial adapter package. Do not remove the adapter from the package. 5. Place the XYNTHA vial on a flat surface. While holding the adapter package, place the vial adapter over the XYNTHA vial and press down firmly on the package until the adapter spike penetrates the vial stopper. 6. Grasp the plunger rod as shown in the diagram. Avoid contact with the shaft of the plunger rod. Attach the threaded end of the plunger rod to the diluent syringe plunger by pushing and turning firmly. 7. Break off the tamper-resistant plastic tip cap from the diluent syringe by snapping the perforation of the cap. Do not touch the inside of the cap or the syringe tip. The diluent syringe may need to be recapped (if not administering reconstituted XYNTHA immediately), so place the cap on its top on a clean surface in a spot where it would be least likely to become environmentally contaminated. 8. Lift the package away from the adapter and discard the package. 9. Place the XYNTHA vial, with the adapter attached, on a flat surface. Connect the diluent syringe to the vial adapter by inserting the tip into the adapter opening while firmly pushing and turning the syringe clockwise until secured. 10. Slowly depress the plunger rod to inject all the diluent into the XYNTHA vial. 11. Without removing the syringe, gently swirl the contents of the XYNTHA vial until the powder is dissolved. Note: The final solution should be inspected visually for particulate matter before administration. The solution should be clear to slightly opalescent and colorless. If it is not, discard the solution and use a new kit. 12. Invert the XYNTHA vial and slowly draw the solution into the syringe. 13. Detach the syringe from the vial adapter by gently pulling and turning the syringe counterclockwise. Discard the empty XYNTHA vial with the adapter attached. Note: If the solution is not used immediately, carefully replace the syringe cap. Do not touch the syringe tip or the inside of the cap. Store the reconstituted solution at room temperature prior to administration, but use within 3 hours after reconstitution. XYNTHA, when reconstituted, contains polysorbate 80, which is known to increase the rate of di-(2-ethylhexyl) phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of XYNTHA, including storage time elapsed in a PVC container following reconstitution. The tubing of the infusion set included with this kit does not contain DEHP. Administration For intravenous infusion after reconstitution only. Inspect the final XYNTHA solution visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be clear to slightly opalescent and colorless. If it is not, discard the solution and use a new kit. Use the tubing and the prefilled diluent syringe provided in this kit or a single sterile disposable plastic syringe. Do not administer XYNTHA in the same tubing or container with other medicinal products. 1. Attach the syringe to the luer end of the infusion set tubing provided. 2. Apply a tourniquet and prepare the injection site by wiping the skin well with an alcohol swab provided in the kit. 3. Remove the protective needle cover and perform venipuncture. Insert the needle on the infusion set tubing into the vein, and remove the tourniquet. Verify proper needle placement. 4. Inject the reconstituted XYNTHA product intravenously over several minutes. The rate of administration should be determined by the patient's comfort level. 5. After infusing XYNTHA, remove and discard the infusion set. The amount of drug product left in the infusion set will not affect treatment. Note: Dispose of all unused solution, the empty vial(s), and other used medical supplies in an appropriate container. Use Of A XYNTHA Vial Kit With A XYNTHA SOLOFUSE™ Kit These instructions are for the use of only one XYNTHA Vial Kit with one XYNTHA SOLOFUSE™ Kit. For further information, please contact the Medical Information Department at Wyeth Pharmaceuticals, 1-800-438-1985. 1. Reconstitute the XYNTHA vial using the instructions described in Preparation and Reconstitution [see Preparation and Reconstitution]. 2. Detach the empty diluent syringe from the vial adapter by gently turning and pulling the syringe counterclockwise, leaving the contents in the XYNTHA vial with the vial adapter in place. 3. Reconstitute the XYNTHA SOLOFUSE™ using the instructions included with the product kit, remembering to remove most, but not all, of the air from the drug product chamber. 4. After removing the protective blue vented cap, connect the XYNTHA SOLOFUSE™ to the vial adapter by inserting the tip into the adapter opening while firmly pushing and turning the syringe clockwise until secured. 5. Slowly depress the plunger rod of the XYNTHA SOLOFUSE™ until the contents empty into the XYNTHA vial. The plunger rod may move back slightly after release. 6. Detach and discard the empty XYNTHA SOLOFUSE™ from the vial adapter. Note: If the syringe turns without detaching from the vial adapter, grasp the white collar and turn. 7. Connect a sterile 10 milliliter or larger luer lock syringe to the vial adapter. Inject some air into the vial to make withdrawing the vial contents easier. 8. Invert the vial and slowly draw the solution into the large luer lock syringe. 9. Detach the syringe from the vial adapter by gently turning and pulling the syringe counterclockwise. Discard the vial with the adapter attached. 10. Attach the infusion set to the large luer lock syringe as directed [see Administration]. HOW SUPPLIED Dosage Forms And Strengths XYNTHA is available as a white to off-white lyophilized powder in the following nominal dosages: 250 International Units 500 International Units 1000 International Units 2000 International Units Each XYNTHA vial has the actual recombinant factor VIII (rFVIII) potency in International Units stated on the label. XYNTHA® is supplied in kits that include single-use vials containing nominally 250, 500, 1000, or 2000 International Units lyophilized powder per vial: 250 International Units Kit: NDC 58394-012-01 500 International Units Kit: NDC 58394-013-01 1000 International Units Kit: NDC 58394-014-01 2000 International Units Kit: NDC 58394-015-01 Each XYNTHA Vial Kit contains: one prefilled diluent syringe containing 4 mL 0.9% Sodium Chloride with plunger rod for assembly, one vial adapter, one sterile infusion set, two alcohol swabs, one bandage, one gauze pad, and one package insert. Actual factor VIII activity in International Units is stated on the label of each XYNTHA vial. Storage And Handling Store XYNTHA under refrigeration at a temperature of 2° to 8°C (36° to 46°F) for up to 36 months from the date of manufacture until the expiration date stated on the label. Within the expiration date, XYNTHA also may be stored at room temperature not to exceed 25°C (77°F) for up to 3 months. After room temperature storage, XYNTHA can be returned to the refrigerator until the expiration date. Do not store XYNTHA at room temperature and return it to the refrigerator more than once. Clearly record the starting date at room temperature storage in the space provided on the outer carton. At the end of the 3-month period, immediately use, discard, or return the product to refrigerated storage. The diluent syringe may be stored at 2° to 25°C (36° to 77°F). Do not use XYNTHA after the expiration date. Do not freeze. (Freezing may damage the prefilled diluent syringe.) During storage, avoid prolonged exposure of XYNTHA vial to light. Store the reconstituted solution at room temperature prior to administration. Administer XYNTHA within 3 hours after reconstitution. REFERENCES 2. Hoyer LW. Hemophilia A. N Engl J Med. 1994;330:38–47. Manufactured by: Wyeth Pharmaceuticals, Inc A subsidiary of Pfizer Inc., Philadelphia, PA 19101. Revised: 3/2015

INDICATIONS ReFacto® Antihemophilic Factor (Recombinant) is indicated for the control and prevention of hemorrhagic episodes and for surgical prophylaxis in patients with hemophilia A (congenital factor VIII deficiency or classic hemophilia). ReFacto (antihemophilic factor) is indicated for short-term routine prophylaxis to reduce the frequency of spontaneous bleeding episodes. The effect of regular routine prophylaxis on long-term morbidity and mortality is unknown. ReFacto (antihemophilic factor) can be of a significant therapeutic value for treatment of hemophilia A in certain patients with inhibitors to factor VIII11. In clinical studies of ReFacto (antihemophilic factor) , study subjects who developed inhibitors on study continued to manifest a clinical response when inhibitor titers were < 10 BU. When an inhibitor is present, the dosage requirement of factor VIII is variable. The dosage can be determined only by a clinical response and by monitoring of circulating factor VIII levels after treatment (see DOSAGE AND ADMINISTRATION). ReFacto (antihemophilic factor) does not contain von Willebrand factor and therefore is not indicated in von Willebrand's disease. DOSAGE AND ADMINISTRATION Treatment with ReFacto® Antihemophilic Factor (Recombinant) should be initiated under the supervision of a physician experienced in the treatment of hemophilia A. The labeled potency of ReFacto (antihemophilic factor) is based on the European Pharmacopoeial chromogenic substrate assay, whereas other factor VIII products are labeled based on the one-stage clotting assay. With recombinant factor VIII products, the chromogenic assay typically yields results which are higher than the results obtained with the one-stage clotting assay. When switching between products it is important to individually titrate each patient's dose in order to ensure an adequate therapeutic response (see PRECAUTIONS, General). Results of a comparative study that evaluated the effect of phospholipids on the one-stage clotting and chromogenic assays showed that the one-stage clotting assay gave results that were approximately 50% of the values obtained with the chromogenic assay (see CLINICAL PHARMACOLOGY). In addition, in clinical trials of ReFacto (antihemophilic factor) use in the surgical setting in which multiple laboratories were used for plasma sample analysis, the ratio of factor VIII activity results as measured by a local laboratory one-stage clotting assay and the central laboratory chromogenic substrate assay was 0.8 (0.2-3.0). When monitoring patients' factor VIII activity levels during treatment, the available clinical data suggest that either assay may be used. Most patients in clinical trials were monitored with the one-stage clotting assay (see CLINICAL PHARMACOLOGY). It is necessary to adhere to the incubation/activation times and other test conditions as specified by the assay manufacturers. Dosage and duration of treatment depend on the severity of the factor VIII deficiency, the location and extent of bleeding, and the patient's clinical condition. Doses administered should be titrated to the patient's clinical response. In the presence of an inhibitor, higher doses may be required. Precise monitoring of the replacement therapy by means of coagulation analysis (plasma factor VIII activity) is recommended, particularly for surgical intervention. One international unit (IU) of factor VIII activity corresponds approximately to the quantity of factor VIII in one mL of normal human plasma. The calculation of the required dosage of factor VIII is based upon the empirical finding that, on average, 1 IU of factor VIII per kg body weight raises the plasma factor VIII activity by approximately 2 IU/dL per IU/kg administered. The required dosage is determined using the following formula: Required units = body weight (kg) x desired factor VIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL) The following chart can be used to guide dosing in bleeding episodes and surgery: Type of Hemorrhage Factor VIII Level Required (IU/dL or % of normal) Frequency of Doses (h)/ Duration of Therapy (d) Minor Early hemarthrosis, minor muscle or oral bleeds. 20–40 Repeat every 12 to 24 hours as necessary until resolved. At least 1 day, depending upon the severity of the hemorrhage. Moderate Hemorrhages into muscles. Mild trauma capitis. Minor operations including tooth extraction. Hemorrhages into the oral cavity. 30–60 Repeat infusion every 12–24 hours for 3–4 days or until adequate local hemostasis is achieved. For tooth extraction a single infusion plus oral antifibrinolytic therapy within 1 hour may be sufficient. Major Gastrointestinal bleeding. Intracranial, intra-abdominal or intrathoracic hemorrhages. Fractures. Major operations. 60–100 Repeat infusion every 8–24 hours until threat is resolved or in the case of surgery, until adequate local hemostasis is achieved. For short-term routine prophylaxis to prevent or reduce the frequency of spontaneous musculoskeletal hemorrhage in patients with hemophilia A, ReFacto (antihemophilic factor) should be given at least twice a week. In some cases, especially pediatric patients, shorter dosage intervals or higher doses may be necessary. Pharmacokinetic/pharmacodynamic modeling, based on pharmacokinetic data from 185 infusions in 102 PTPs, predicts that routine prophylactic dosing 3 times per week may be associated with a lower bleeding risk than with dosing twice weekly. No randomized comparison of different doses or frequency regimens of ReFacto (antihemophilic factor) for routine prophylaxis has been performed. In clinical studies in PTPs (ages 8-73 years) and PUPs (ages < 1-52 months), the mean dose used per infusion for routine prophylaxis was 29 ± 11 IU/kg and 53 ± 22 IU/kg, respectively. Patients using ReFacto (antihemophilic factor) should be monitored for the development of factor VIII inhibitors. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor VIII inhibitor is present. If the inhibitor is present at levels less than 10 Bethesda Units, administration of additional antihemophilic factor may neutralize the inhibitor. ReFacto (antihemophilic factor) is administered by IV infusion after reconstitution of the lyophilized powder with Sodium Chloride Diluent (provided). ReFacto (antihemophilic factor) , when reconstituted, contains polysorbate-80, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of ReFacto (antihemophilic factor) , including storage time elapsed in a PVC container following reconstitution. It is important that the recommendations in DOSAGE AND ADMINISTRATION be followed closely. Instructions for Use Patients should follow the specific reconstitution and administration procedures provided by their physicians. The procedures below are provided as general guidelines for the reconstitution and administration of ReFacto (antihemophilic factor) . Reconstitution Always wash your hands before performing the following procedures. Aseptic technique (meaning clean and germ free) should be used during the reconstitution procedure. All components used in the reconstitution and administration of this product should be used as soon as possible after opening their sterile containers to minimize unnecessary exposure to the atmosphere. ReFacto® Antihemophilic Factor (Recombinant) is administered by intravenous (IV) infusion after reconstitution with the supplied diluent (0.9% Sodium Chloride Diluent, 4 mL disposable syringe for drug diluent use with ReFacto Antihemophilic Factor [Recombinant]) syringe. 1. Allow the vials of lyophilized ReFacto (antihemophilic factor) and the pre-filled diluent syringe to reach room temperature. 2. Remove the plastic flip-top cap from the ReFacto (antihemophilic factor) vial to expose the central portions of the rubber stopper. 3. Wipe the top of the vial with the alcohol swab provided, or use another antiseptic solution, and allow to dry. After cleaning, do not touch the rubber stopper with your hand or allow it to touch any surface. 4. Peel back the cover from the clear plastic vial adapter package. Do not remove the adapter from the package. 5. While holding the adapter package, place the vial adapter over the vial and press down firmly on the package until the adapter spike penetrates the vial stopper. 6. Grasp the plunger rod per the diagram. Avoid contact with the shaft of the plunger rod. Attach the threaded end of the plunger rod to the diluent syringe plunger by pushing and turning firmly. 7. Break off the tamper-resistant plastic tip cap from the diluent syringe by snapping the perforation of the cap. Do not touch the inside of the cap or the syringe tip. Place the cap on its top on a clean surface in a spot where it would be least likely to become environmentally contaminated. The cap may need to be replaced (if not administering reconstituted ReFacto (antihemophilic factor) immediately). 8. Lift the package away from the adapter and discard the package. 9. Place the vial on a flat surface. Connect the diluent syringe to the vial adapter by inserting the tip into the adapter opening while firmly pushing and turning the syringe clockwise until secured. 10. Slowly depress the plunger rod to inject all the diluent into the ReFacto (antihemophilic factor) vial. 11. Without removing the syringe, gently swirl the contents of the vial until the powder is dissolved. 12. Inspect the final solution for specks before administration. The solution should appear clear and colorless. Note: If you use more than one vial of ReFacto (antihemophilic factor) per infusion, reconstitute each vial as per the previous instructions. 13. Invert the vial and slowly draw the solution into the syringe. Note: If you prepared more than one vial of ReFacto (antihemophilic factor) , remove the diluent syringe from the vial adapter, leaving the vial adapter attached to the vial. Quickly attach a separate large luer lock syringe and draw back the reconstituted contents as instructed above. Repeat this procedure with each vial in turn. Do not detach the diluent syringes or the large luer lock syringe until you are ready to attach the large luer lock syringe to the next vial adapter. 14. Detach the syringe from the vial adapter by gently pulling and turning the syringe counter-clockwise. Discard the vial with the adapter attached. Note: If the solution is not to be used immediately, the syringe cap should be carefully replaced. Do not touch the syringe tip or the inside of the cap. ReFacto (antihemophilic factor) should be administered within 3 hours after reconstitution. The reconstituted solution may be stored at room temperature prior to administration. Administration (Intravenous Injection) ReFacto® Antihemophilic Factor (Recombinant) should be administered using the tubing provided in this kit, and the pre-filled diluent syringe provided or a single sterile disposable plastic syringe. In addition, the solution should be withdrawn from the vial using the vial adapter. 1. Attach the syringe to the luer end of the infusion set tubing provided and perform venipuncture as instructed by your physician. In the absence of incompatibility studies, reconstituted ReFacto (antihemophilic factor) should not be administered in the same tubing or container with other medicinal products. In vitro studies suggest that factor VIII may adsorb to the internal surfaces of some infusion equipment. After reconstitution, ReFacto (antihemophilic factor) should be injected intravenously over several minutes. The rate of administration should be determined by the patient's comfort level. Following completion of ReFacto (antihemophilic factor) treatment, remove the infusion set and discard. The amount of drug product remaining in the infusion set is not clinically significant. Dispose of all unused solution, the empty vial(s), and the used needles and syringes in an appropriate container for throwing away waste that might hurt others if not handled properly. Storage Product as packaged for sale: ReFacto® Antihemophilic Factor (Recombinant) should be stored under refrigeration at a temperature of 2° to 8°C (36° to 46°F). ReFacto (antihemophilic factor) may also be stored at room temperature not to exceed 25°C (77°F) for up to 3 months, until the expiration date. The patient should write in the space provided on the outer carton the date the product was placed at room temperature. At the end of the 3-month period, the product should not be put back into the refrigerator, but should be used immediately or discarded. Freezing should be avoided to prevent damage to the pre-filled diluent syringe. During storage, avoid prolonged exposure of ReFacto® (antihemophilic factor) vial to light. Do not use ReFacto (antihemophilic factor) after the expiry date on the label. Product after reconstitution: The product does not contain a preservative and should be used within 3 hours. HOW SUPPLIED ReFacto® Antihemophilic Factor (Recombinant) is supplied in kits that include single-use (4 mL size, dried) vials which contain nominally 250, 500, 1000 or 2000 IU per vial: 250 IU Kit: NDC 58394–007–04 500 IU Kit: NDC 58394–006–04 1000 IU Kit: NDC 58394–005–04 2000 IU Kit: NDC 58394–011–04 Actual factor VIII activity in IU is stated on the label of each ReFacto® Antihemophilic Factor (Recombinant) vial. In addition, each ReFacto® Antihemophilic Factor (Recombinant) kit contains: one pre-filled diluent syringe containing 4 mL 0.9% Sodium Chloride with plunger rod for assembly, one vial adapter, one sterile infusion set, two alcohol swabs, one bandage, one gauze, and one package insert. REFERENCES 11. Kessler CM. An Introduction to Factor VIII Inhibitors: The Detection and Quantitation. American Journal of Medicine. 1991;91(Supplement 5A):1S-5S. This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Manufactured and Distributed by: Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101. Rev 12/07.

INDICATIONS OBIZUR, Antihemophilic Factor (Recombinant), Porcine Sequence, is a recombinant DNA derived, antihemophilic factor indicated for the treatment of bleeding episodes in adults with acquired hemophilia A. Limitations of Use Safety and efficacy of OBIZUR has not been established in patients with baseline anti- porcine factor VIII inhibitor titer greater than 20 BU. OBIZUR is not indicated for the treatment of congenital hemophilia A or von Willebrand disease. DOSAGE AND ADMINISTRATION For intravenous use after reconstitution only Dose Dose, dosing frequency, and duration of treatment with OBIZUR depend on the location and severity of bleeding episode, target factor VIII levels, and the patient's clinical condition. Monitor replacement therapy in cases of major surgery or life-threatening bleeding episodes. Each vial of OBIZUR has the recombinant porcine factor VIII potency in units stated on the vial. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses. Titrate dose and frequency based on factor VIII recovery levels and individual clinical response. A guide for dosing OBIZUR for the treatment and prevention of bleeding episodes is provided in Table 1. Maintain the factor VIII activity within the target range. Plasma levels of factor VIII should not exceed 200% of normal or 200 units per dL. Table 1 : Dosing for Treatment of Bleeding Episodes Type of Bleeding Factor VIII Level Required (Units per dL or % of normal) Initial Dose (Units per kg) Subsequent Dose Frequency and Duration of Subsequent Dosing Minor and Moderate Superficial muscle/no neurovascular compromise, and joint 50-100 200 Titrate subsequent doses to maintain recommended factor VIII trough levels and individual clinical response Dose every 4 to 12 hours, frequency may be adjusted based on clinical response and measured factor VIII levels Major Moderate to severe intramuscular bleeding, retroperitoneal, gastrointestinal, intracranial 100-200 (To treat an acute bleed) 50-100 (After acute bleed is controlled, if required) Reconstitution Use aseptic technique during the reconstitution procedure. If the patient needs more than one vial of OBIZUR per injection, reconstitute each vial according to the following instructions: Bring the OBIZUR vial and the pre-filled diluent syringe to room temperature. Remove the plastic cap from the OBIZUR vial (Figure A). Wipe the rubber stopper with an alcohol swab (not supplied) and allow it to dry prior to use. Peel back the cover of the vial adapter package (Figure B). Do not to touch the luer-lock (tip) in the center of the vial adapter. Do not remove the vial adapter from the plastic package. Place the vial adapter package on a clean surface with the luer-lock pointing up. Snap off the tamper resistant cap of the pre-filled syringe (Figure C). While firmly holding the vial adapter package, connect the pre-filled syringe to the vial adapter by pushing the syringe tip down onto the luer lock in the center of the vial adapter, and turning it clockwise until the syringe is secured. Do not over tighten (Figure D). Remove the plastic package (Figure E). Place the OBIZUR vial on a clean, flat, hard surface. Place the vial adapter over the OBIZUR vial and firmly push the filter spike of the vial adapter through the center of the OBIZUR vial's rubber circle until the clear plastic cap snaps onto the vial (Figure F). Push the plunger down to slowly inject all of the diluent from the syringe into the OBIZUR vial. Gently swirl (in a circular motion) the OBIZUR vial without removing the syringe until all of the powder is fully dissolved (Figure G). The reconstituted solution should be inspected visually for particulate matter before administration. Do not use if particulate matter or discoloration is observed. With one hand hold the vial and vial adapter, and with the other hand firmly grasp the barrel of the pre-filled syringe and in a counterclockwise motion unscrew the syringe from the vial adapter (Figure H). Use OBIZUR within 3 hours after reconstitution when stored at room temperature. Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Administration For intravenous injection only Inspect the reconstituted OBIZUR solution for particulate matter and discoloration prior to administration. The solution should be clear and colorless in appearance. Do not administer if particulate matter or discoloration is observed. Do not administer OBIZUR in the same tubing or container with other medicinal products for infusion. 1. Once all vials have been reconstituted, connect a large syringe to the vial adapter by gently pushing the syringe tip down onto the luer lock in the center of the vial adapter, and turning clockwise until the syringe is secured. 2. Invert the vial; push the air in the syringe into the vial and withdraw the reconstituted OBIZUR into the syringe (Figure I). Figure I 3. Unscrew the large syringe counterclockwise from the vial adapter, and repeat this process for all reconstituted vials of OBIZUR until the total volume to be administered is reached. 4. Administer the reconstituted OBIZUR intravenously at a rate of 1 to 2 mL per minute. HOW SUPPLIED Dosage Forms And Strengths OBIZUR is available as a white lyophilized powder in single-use glass vials containing nominally 500 units per vial. OBIZUR is supplied as a white lyophilized powder in single-use vials in the following package sizes: Nominal Strength Package Size Kit NDC 500 units 1-vial package 0944-5001-01 500 units 5-vial package 0944-5001-05 500 units 10-vial package 0944-5001-10 Each package contains one package insert and appropriate number of each of the components listed below correlating to the vial package size: Single-use vial of OBIZUR [NDC 0944-5011-01] Pre-filled syringe with 1 mL Sterile Water for Injection [NDC 0944-0011-01] Vial adapter with filter The actual amount of OBIZUR in units is stated on the label of each vial. Storage And Handling Store OBIZUR at refrigeration temperature of 2° to 8°C [36° to 46°F]. Do not freeze. Store vials in the original package to protect from light. Do not use beyond the expiration date printed on the carton or vial. Use OBIZUR within 3 hours after reconstitution. Discard any unused reconstituted product if not used within 3 hours after reconstitution. Do not use OBIZUR if the reconstituted solution is cloudy or has particulate matter. Manufactured by: Baxter Healthcare Corporation Westlake Village, CA 91362 USA. Revised: October 2014

INDICATIONS ADYNOVATE, Antihemophilic Factor (Recombinant), PEGylated, is a human antihemophilic factor indicated in adolescent and adult patients (12 years and older) with hemophilia A (congenital factor VIII deficiency) for: On-demand treatment and control of bleeding episodes Routine prophylaxis to reduce the frequency of bleeding episodes ADYNOVATE is not indicated for the treatment of von Willebrand disease. DOSAGE AND ADMINISTRATION For intravenous use after reconstitution only. Dose Each vial label of ADYNOVATE states the actual factor VIII potency in international units. This may be more or less than the nominal vial potency/content. One international unit corresponds to the activity of factor VIII contained in one milliliter of normal human plasma. Initiate treatment under the supervision of a physician experienced in the treatment of hemophilia A. Dosage and duration of treatment depend on the severity of factor VIII deficiency, the location and extent of the bleeding, and the patient's clinical condition. Careful monitoring of replacement therapy is necessary in cases of serious or life-threatening bleeding episodes. Potency assignment is determined using a one-stage clotting assay. Plasma factor VIII levels can be monitored clinically using a one-stage clotting assay. Calculate the dose of ADYNOVATE based on the empirical finding that one international unit of ADYNOVATE per kg body weight increases the plasma factor VIII level by 2 IU per dL of plasma. Use the following formula to estimate the expected in vivo peak increase in factor VIII level expressed as IU per dL (or % of normal) and the dose to achieve a desired in vivo peak increase in factor VIII level: Estimated Increment of factor VIII (IU/dL or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg) Dose (IU) = Body Weight (kg) x Desired factor VIII Rise (IU/dL or % of Normal) x 0.5 (IU/kg per IU/dL) Patients vary in their pharmacokinetic (e.g., clearance, half-life, in vivo recovery) and clinical response. Base the dose and frequency of ADYNOVATE on the individual clinical response. On-demand Treatment and Control of Bleeding Episodes A guide for dosing of ADYNOVATE for the on-demand treatment and control of bleeding episodes is provided in Table 1. Maintain plasma factor VIII activity level at or above the described plasma levels (in IU per dL or % of normal). Table 1: Dosing for On-demand Treatment and Control of Bleeding Episodes Type of Bleeding Target Factor VIII Level (IU/dL or % of normal) Dosea (IU/kg) Frequency of Dosing (hours) Duration of Therapy Minor Early hemarthrosis, mild muscle bleeding, or mild oral bleeding episode. 20-40 10-20 12-24 Until the bleeding is resolved. Moderate Muscle bleeding, moderate bleeding into the oral cavity, definite hemarthroses, and known trauma. 30-60 15-30 12-24 Until the bleeding is resolved. Major Significant gastrointestinal bleeding, intracranial, intra-abdominal or intrathoracic bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces or iliopsoas sheath, fractures, head trauma. 60-100 30-50 8-24 Until bleeding is resolved. aDose (IU/kg) = Desired factor VIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL) Routine Prophylaxis Administer 40-50 IU per kg body weight 2 times per week. Adjust the dose based on the patient's clinical response. Preparation And Reconstitution Preparation Use aseptic technique (clean and germ free) and a flat work surface during the reconstitution procedure. Reconstitution 1. Allow the vials of ADYNOVATE and diluent to reach room temperature before use. 2. Remove plastic caps from the ADYNOVATE and diluent vials. 3. Cleanse rubber stoppers with a sterile alcohol prep pad and allow to dry prior to use. Figure A 4. Open the BAXJECT II Hi-Flow device package by peeling away the lid, without touching the inside (Figure A). Do not remove the device from the package. 5. Turn the package over. Press straight down to fully insert the clear plastic spike through the diluent vial stopper (Figure B). Figure B 6. Grip the BAXJECT II Hi-Flow package at its edge and pull the package off the device (Figure C). Do not remove the blue cap from the BAXJECT II Hi-Flow device. Do not touch the exposed purple plastic spike. Figure C 7. Turn the system over so that the diluent vial is on top. Quickly insert the purple plastic spike fully into the ADYNOVATE vial stopper by pushing straight down (Figure D). The vacuum will draw the diluent into the ADYNOVATE vial. Figure D 8. Swirl gently until ADYNOVATE is completely dissolved. Do not refrigerate after reconstitution. 9. If the dose requires more than one vial of ADYNOVATE, reconstitute each vial using the above steps. Use a different BAXJECT II Hi-Flow device to reconstitute each vial of ADYNOVATE and diluent. Administration Visually inspect the reconstituted ADYNOVATE solution for particulate matter and discoloration prior to administration, whenever solution and container permit. The final ADYNOVATE solution should be clear and colorless. Do not use if particulate matter or discoloration is observed. Administer ADYNOVATE as soon as possible, but no later than 3 hours after reconstitution. Administration Steps 1. Remove the blue cap from the BAXJECT II Hi-Flow device. Connect the syringe to the BAXJECT II Hi-Flow device (Figure E). Use of a Luer-lock syringe is recommended. Do not inject air. Figure E 2. Turn the system upside down (ADYNOVATE vial now on top). Draw the factor concentrate into the syringe by pulling the plunger back slowly (Figure F). Figure F 3. If a patient is to receive more than one vial of ADYNOVATE, the contents of multiple vials may be drawn into the same syringe. 4. Disconnect the syringe; attach a suitable needle. 5. Inject ADYNOVATE intravenously over a period of less than or equal to 5 minutes (maximum infusion rate 10 mL per min). HOW SUPPLIED Dosage Forms And Strengths ADYNOVATE is a lyophilized powder in single-use vials containing nominally (approximately) 250, 500, 1000, and 2000 International Units (IU, units). The actual factor VIII potency/content is labeled on each ADYNOVATE vial. The potency assignment employs a factor VIII concentrate standard that is referenced to a WHO (World Health Organization) international standard for factor VIII concentrates and is evaluated by appropriate methodology to ensure accuracy of the results. ADYNOVATE is supplied in packages comprised of a single-use vial containing nominally (approximately) 250, 500, 1000, or 2000 international units (IU) of factor VIII potency, a diluents vial containing 5 mL of sterile Water for Injection (sWFI), and a BAXJECT II Hi-Flow Needleless Transfer Device. Components not made with natural rubber latex. Nominal Strength Actual Factor VIII Potency Range Carton NDC (Includes 5 mL sWFI Diluent) 250 IU 200-400 IU per vial 0944-4252-02 500 IU 401-800 IU per vial 0944-4254-02 1000 IU 801-1250 IU per vial 0944-4256-02 2000 IU 1251-2500 IU per vial 0944-4258-02 Actual factor VIII activity in IU is stated on the label of each ADYNOVATE carton and vial. Storage And Handling Store ADYNOVATE in powder form at 2°to 8°C (36°to 46°F). Do not freeze. ADYNOVATE may be stored at room temperature not to exceed 30°C (86°F) for a period of up to 1 month not to exceed the expiration date. If stored at room temperature, write the date on the carton when ADYNOVATE is removed from refrigeration. After storage at room temperature, do not return the product to the refrigerator. Do not use beyond expiration date printed on the carton or vial. Store vials in their original box and protect them from extreme exposure to light. After reconstitution, do not refrigerate the solution. Use the reconstituted solution immediately or within 3 hours after reconstitution. Discard any remaining solution. Baxalta US Inc. Westlake Village, CA 91362 USA, U.S. Revised: Nov 2015

INDICATIONS ELOCTATE, Antihemophilic Factor (Recombinant), Fc Fusion Protein, is a recombinant DNA derived, antihemophilic factor indicated in adults and children with Hemophilia A (congenital Factor VIII deficiency) for: Control and prevention of bleeding episodes, Perioperative management (surgical prophylaxis), Routine prophylaxis to prevent or reduce the frequency of bleeding episodes. ELOCTATE is not indicated for the treatment of von Willebrand disease. DOSAGE AND ADMINISTRATION For intravenous use after reconstitution only. Dosing Guidelines Dose and duration of treatment depend on the severity of the Factor VIII deficiency, the location and extent of bleeding, and the patient's clinical condition. Careful monitoring of replacement therapy is necessary in cases of major surgery or life-threatening bleeding episodes. Each vial label of ELOCTATE states the Factor VIII potency in international units (IU). One IU corresponds to the activity of Factor VIII contained in one milliliter of normal human plasma. Potency assignment is determined using a chromogenic substrate assay. A field study1 has indicated that plasma Factor VIII levels can be monitored using either a chromogenic substrate assay or a one stage clotting assay routinely used in US clinical laboratories. Calculation of the required dose of Factor VIII is based on the empirical finding that 1 IU of Factor VIII per kg body weight raises the plasma Factor VIII level by 2 IU/dL. The expected in vivo peak increase in Factor VIII level expressed as IU/dL (or % of normal) is estimated using the following formula: Estimated Increment of Factor VIII (IU/dL or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg) The dose to achieve a desired in vivo peak increase in Factor VIII level may be calculated using the following formula: Dose (IU) = body weight (kg) x Desired Factor VIII Rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL) Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses. Base the dose and frequency of ELOCTATE on the individual clinical response. Dose adjustment may be necessary in pediatric patients under six years of age [see Use In Specific Populations]. For patients six years of age or older, dose adjustment is not usually required. Control and Prevention of Bleeding Episodes A guide for dosing ELOCTATE for the control and prevention of bleeding episodes is provided in Table 1. Consideration should be given to maintaining a Factor VIII activity at or above the target range. Table 1: Dosing for Control and Prevention of Bleeding Episodes Type of Bleeding Factor VIII Level Required (IU/dL or % of normal) Dose (IU/kg) Frequency of Dosing (hours) Duration of Therapy (days) Minor and Moderate Joint, superficial muscle/no neurovascular compromise (except iliopsoas), deep laceration and renal, superficial soft tissue, mucous membranes 40-60 20-30 Repeat every 24-48 hours (12 to 24 hours for patients less than 6 years of age) Until the bleeding episode is resolved Major Life or limb threatening hemorrhage, iliopsoas and deep muscle with neurovascular injury, retroperitoneum, intracranial, or gastrointestinal 80-100 40-50 Repeat every 12-24 hours (8 to 24 hours for patients less than 6 years of age) Until bleeding is resolved (approximately 7-10 days) Perioperative Management A guide for dosing ELOCTATE during surgery (perioperative management) is provided in Table 2. Consideration should be given to maintaining a Factor VIII activity at or above the target range. Table 2: Dosing for Perioperative Management Type of Surgery Factor VIII Level Required (IU/dL or % of normal) Dose (IU/kg) Frequency of Dosing (hours) Duration of Therapy (days) Minor Uncomplicated tooth extraction 50-80 25-40 Repeat every 24 hours (12-24 hours for patients less than 6 years of age) At least 1 day until healing is achieved Major Intracranial, intra-abdominal, or joint replacement surgery 80-120 (pre- and postoperative) Preoperative: 40-60 Repeat: 40-50 Pre-operative dose of 40 to 60 IU/kg followed by a repeat dose of 40-50 IU/kg after 8-24 hours (6 to 24 for patients less than 6 years of age) and then every 24 hours to maintain FVIII activity within the target range Until adequate wound healing, then continue therapy for at least 7 days to maintain a Factor VIII activity within the target range Routine Prophylaxis The recommended starting regimen is 50 IU/kg of ELOCTATE administered every 4 days. The regimen may be adjusted based on patient response with dosing in the range of 25-65 IU/kg at 3-5 day intervals. More frequent or higher doses up to 80 IU/kg may be required in children less than 6 years of age. [see CLINICAL PHARMACOLOGY] Preparation And Reconstitution 1. Use aseptic technique (clean and germ free) and a flat work surface during the reconstitution procedure. 2. Allow the vial of ELOCTATE and pre-filled diluent syringe to reach room temperature before use. 3. Remove the plastic cap from the vial and wipe the rubber stopper of the vial with an alcohol wipe. Allow the rubber stopper to dry. 4. Completely remove the backing from the vial adapter package by peeling back the lid. Do not remove the vial adapter from the package or touch the inside of the package of the adapter. 5. Place the vial on a flat and solid surface and use one hand to hold the vial steady. Use the other hand to place the vial adapter over the vial. Place the adapter spike directly above the center of the rubber stopper and push the adapter straight down until the spike punctures the center of the vial stopper and is fully inserted. 6. Lift the package cover away from the vial adapter and discard the cover. 7. Hold the plunger rod at the circular disk. Place the tip of the plunger rod into the end of the syringe. Turn clockwise until it is securely attached. Only use the diluent syringe provided in the ELOCTATE package. 8. With one hand, hold the diluent syringe by the ridged part directly under the cap, with the cap pointing up. Do not use if the cap has been removed or is not securely attached. 9. With your other hand, grasp the cap and bend it at a 90° angle until it snaps off. After the cap snaps off, you will see the glass tip of the syringe. Do not touch the glass tip of the syringe or the inside of the cap. 10. With the vial sitting on a flat surface, insert the tip of the syringe into the adapter opening. Turn the syringe clockwise until it is securely attached to the adapter. 11. Slowly depress the plunger rod to inject all of the diluent into the vial. The plunger rod may rise slightly after this process. This is normal. 12. With the syringe still connected to the adapter, gently swirl the vial until the product is completely dissolved. Do not shake. The reconstituted solution should be clear to slightly opalescent and colorless. Do not use the reconstituted ELOCTATE if it contains visible particles or is cloudy. 13. Make sure the plunger rod is completely depressed. Turn the vial upside-down. Slowly pull on the plunger rod to draw the solution into the syringe. Be careful not to pull the plunger rod completely out of the syringe. 14. Gently unscrew the syringe from the vial adapter and dispose of the vial with the adapter still attached. Do not touch the syringe tip or the inside of the cap. 15. Use the reconstituted ELOCTATE as soon as possible, but no later than 3 hours after reconstitution. Do not touch the glass tip of the syringe if not used immediately after reconstitution. Protect from direct sunlight. Do not refrigerate after reconstitution. To combine two or more vials of ELOCTATE, after step 12 above, follow these pooling steps: Remove the diluent syringe from the vial adapter by turning it counterclockwise until it is completely detached. Leave the vial adapter attached to the vial, as it is needed for attaching a large luer lock syringe (not included in kit). Do not detach the diluent syringe until ready to attach the large luer-lock syringe. Attach a separate, large luer-lock syringe by turning clockwise until it is securely in place. Slowly pull on the plunger rod to draw the solution into the syringe. Repeat this pooling procedure with each vial that is needed to obtain the required dose. When pooling, do not detach the large luer-lock syringe until ready to attach it to the next vial (with vial adapter attached). Once you have pooled the required dose, proceed to administration using the large luer-lock syringe. Administration For Intravenous Injection Only Inspect the reconstituted ELOCTATE solution visually for particulate matter and discoloration prior to administration. Do not use if particulate matter or discoloration is observed. Do not administer reconstituted ELOCTATE in the same tubing or container with other medications. Administration Steps Attach the syringe to the connector end of the infusion set tubing by turning clockwise until it is securely in place. Depress the plunger until all air is removed from the syringe and ELOCTATE has reached the end of the infusion set tubing. Do not push ELOCTATE solution through the needle. Remove the protective needle cover from the infusion set tubing. Perform intravenous bolus infusion. The rate of administration should be determined by the patient's comfort level, and no faster than 10 ml per minute. After infusing ELOCTATE, remove and properly discard the infusion set. HOW SUPPLIED Dosage Forms And Strengths ELOCTATE is available as a lyophilized powder in single use vials containing nominally 250, 500, 750, 1000, 1500, 2000, or 3000 international units (IU) per vial. The actual Factor VIII potency is labeled on each ELOCTATE vial. ELOCTATE is supplied in kits comprising a single use vial containing nominally, 250, 500, 750, 1000, 1500, 2000, or 3000 international units (IU) of Factor VIII potency, a pre-filled syringe with 3 mL sterile water for injection, and a sterile vial adapter (reconstitution device). The actual amount of ELOCTATE in IU is stated on the label and carton of each vial. Strength Kit NDC Number 250 IU 64406-801-01 500 IU 64406-802-01 750 IU 64406-803-01 1000IU 64406-804-01 1500IU 64406-805-01 2000IU 64406-806-01 3000 IU 64406-807-01 Storage And Handling Prior To Reconstitution Store ELOCTATE in the original package to protect the ELOCTATE vials from light. Store ELOCTATE in powder form at 2°C to 8°C (36°F to 46°F). Do not freeze to avoid damage to the pre-filled diluent syringe. ELOCTATE may be stored at room temperature, not to exceed 30°C (86°F), for a single period of up to 6 months, within the expiration date printed on the label. If stored at room temperature, record the date that ELOCTATE is removed from refrigeration on the carton in the area provided. After storage at room temperature, do not return the product to the refrigerator. Do not use beyond the expiration date printed on the vial or 6 months after the date that was written on the carton, whichever is earlier. After Reconstitution The reconstituted product may be stored at room temperature, not to exceed 30°C (86°F), for up to 3 hours. Protect from direct sunlight. After reconstitution, if the product is not used within 3 hours, it must be discarded. Do not use ELOCTATE if the reconstituted solution is cloudy or has particulate matter. Discard any unused ELOCTATE. Manufactured by: Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142 USA. Revised: June 2014

INDICATIONS Novoeight®, Antihemophilic Factor (Recombinant), is indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency or classic hemophilia) for: Control and prevention of bleeding episodes Perioperative management Routine prophylaxis to prevent or reduce the frequency of bleeding episodes Novoeight® is not indicated for the treatment of von Willebrand disease. DOSAGE AND ADMINISTRATION For intravenous injection after reconstitution only. Dose Dosage and duration of treatment depend on the severity of the factor VIII deficiency, on the location and extent of bleeding, and the patient's clinical condition. Careful monitoring of replacement therapy is necessary in cases of major surgery or life-threatening bleeding episodes. Each vial of Novoeight® contains the labeled amount of recombinant factor VIII in international units (IU). One IU of factor VIII activity corresponds to the quantity of factor VIII in one milliliter of normal human plasma. The calculation of the required dosage of factor VIII is based on the empirical finding that one IU of factor VIII per kg body weight raises the plasma factor VIII activity by two IU/dL. This relationship causes a factor of 0.5 to be present in the dose calculation formula shown below. The required dosage can be determined using the following formula: Dosage (IU) = Body Weight (kg) × Desired Factor VIII Increase (IU/dL or % normal) × 0.5 The final dose calculated is expressed as IU Base the dose and frequency of Novoeight® on the individual clinical response. Patients may vary in their pharmacokinetic and clinical responses. Control And Prevention Of Bleeding Episodes A guide for dosing Novoeight® for the control and prevention of bleeding episodes is provided in Table 1. Dosing should aim at maintaining a plasma factor VIII activity level at or above the plasma levels (in % of normal or in IU/dL) outlined in Table 1. Table 1: Dosing for Control and Prevention of Bleeding Episodes Type of Bleeding Episodes Factor VIII Level Required (IU/dL or % of normal) Frequency of Doses (hours) Duration of Therapy (days) Minor Early hemarthrosis, minor muscle or oral bleeding 20-40 12-24 At least 1 day until bleeding resolution is achieved Moderate Muscle bleeding, bleeding into the oral cavity or mild head trauma 30-60 12-24 Until pain and acute disability are resolved (approximately 3-4 days) Major Life or limb threatening hemorrhage, Gastrointestinal bleeding, intracranial, intra-abdominal or intrathoracic bleeding, fractures 60-100 8-24 Until resolution of bleed (approximately 7-10 days) Perioperative Management A guide for dosing Novoeight® during surgery (perioperative management) is provided in Table 2. Consideration should be given to maintaining a plasma factor VIII activity level at or above the plasma levels (in % of normal or in IU/dL) outlined in Table 2. Table 2: Dosing for Perioperative Management Type of Surgery Factor VIII Level Required (IU/dL or % of normal) Frequency of Doses (hours) Duration of Therapy (days) Minor Including tooth extraction 30-60 24 At least 1 day until healing is achieved Major Intracranial, intraabdominal, intrathoracic, or joint replacement surgery 80-100 (pre-and post-operative) 8-24 Until adequate wound healing, then continue therapy for at least 7 days to maintain a factor VIII activity of 30% to 60% (IU/dL) Routine Prophylaxis A guide for dosing Novoeight® for routine prophylaxis is included below in Table 3. Table 3: Dosing for Routine Prophylaxis Patient Population Factor VIII Dose Required (IU/kg) Frequency of Doses Adults and adolescents ( ≥ 12 years) 20-50 3 times weekly 20-40 Every other day Children ( < 12 years) 25-60 3 times weekly 25-50 Every other day Preparation And Reconstitution Always wash hands and ensure that the area is clean before performing the procedures. Use aseptic technique during the reconstitution procedures. If the patient uses more than one vial of Novoeight® per injection, reconstitute each vial according to the following instructions. Overview Of Novoeight® Package The instructions below serve as a general guideline for preparation and reconstitution of Novoeight®. For full instructions, refer to the FDA-approved patient information and Instructions for Use. Reconstitution 1. Bring the Novoeight® vial and the pre-filled diluent syringe to room temperature. Figure A 2. Remove the plastic cap from the Novoeight® vial. Figure B 3. Wipe the rubber stopper on the vial with a sterile alcohol swab and allow it to dry prior to use. 4. Remove the protective paper from the vial adapter. Do not remove the vial adapter from the protective cap. Figure C 5. Place the vial on a flat and solid surface. While holding the protective cap, place the vial adapter over the Novoeight® vial and press down firmly on the protective cap until the vial adapter spike penetrates the rubber stopper. Figure D 6. Remove the protective cap from the vial adapter. Figure E 7. Grasp the plunger rod as shown in the diagram. Attach the plunger rod to the syringe by holding the plunger rod by the wide top end. Turn the plunger rod clockwise into the rubber plunger inside the pre-filled diluent syringe until resistance is felt. Figure F 8. Break off the syringe cap from the pre-filled diluent syringe by snapping the perforation of the cap. Figure G 9. Connect the pre-filled diluent syringe to the vial adapter by turning it clockwise until it is secured. Figure H 10. Push the plunger rod to slowly inject all the diluent into the vial. Figure I 11. Without removing the syringe, gently swirl the Novoeight® vial until all of the powder is dissolved. The reconstituted solution should be inspected visually for particulate matter before administration. Do not use if particulate matter or discoloration is observed. Figure J 12. Use the Novoeight® solution immediately. If not, store the solution in the vial with the vial adapter and the syringe attached, at room temperature ≤ 86°F (30°C) for no longer than 4 hours. Administration For intravenous injection only. Accidental needle stick with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in a sharps container after single-use. Inspect the reconstituted Novoeight® solution visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if particulate matter or discoloration is observed. Do not administer Novoeight® in the same tubing or container with other medicinal products. 1. Invert the Novoeight® vial and slowly draw the solution into the syringe. Figure K 2. Detach the syringe from the vial adapter by turning the syringe counterclockwise. 3. Attach the syringe to the luer end of an infusion needle set. 4. Inject the reconstituted Novoeight® intravenously slowly over 2 to 5 minutes. 5. After injection, safely dispose of the syringe with the infusion set, the vial with the vial adapter, any unused Novoeight® and other waste materials. Caution The pre-filled diluent syringe is made of glass with an internal tip diameter of 0.037 inches, and is compatible with a standard Luer-lock connector. Some needleless connectors for intravenous catheters are incompatible with the glass diluent syringes (for example, certain connectors with an internal spike, such as Clave® /MicroClave®, InVision-Plus®, InVision-Plus CS®, Invision-Plus Junior®, Bionector®), and their use can damage the connector and affect administration. To administer Novoeight® through incompatible needleless connectors, withdraw the reconstituted product into a standard 10 mL sterile Luer-lock plastic syringe. If you encounter any problems with attaching the pre-filled sodium chloride diluent syringe to any Luer-lock compatible device, please contact Novo Nordisk at (844) 303-4448. HOW SUPPLIED Dosage Forms And Strengths Novoeight® is available as a white lyophilized powder in single-use vials containing 250, 500, 1000, 1500, 2000 and 3000 international units per vial. After reconstitution with 4 mL of 0.9% sodium chloride solution, each mL of reconstituted solution contains approximately 62.5, 125, 250, 375, 500 or 750 international units of Novoeight®, respectively. Novoeight® is supplied in packages comprised of a single-use vial containing nominally 250, 500, 1000, 1500, 2000, or 3000 international units (IU) of FVIII potency, a MixPro® pre-filled diluent syringe containing 0.9% sodium chloride solution, and sterile vial adapter with 25 micrometer filter, which serves as a needleless reconstitution device. The actual amount of FVIII potency in IU is stated on each carton and vial. Presentation (Nominal Product Strength) Carton Number Components 250 International Units NDC 0169 7825 01 Novoeight® in single-use vial [NDC 0169-7829-11] Pre-filled sodium chloride diluent in syringe, 4 mL [NDC 0169-7008-98] Vial adapter 500 International Units NDC 0169 7850 01 Novoeight® in single-use vial [NDC 0169-7851-11] Pre-filled sodium chloride diluent in syringe, 4 mL [NDC 0169-7008-98] Vial adapter 1000 International Units NDC 0169 7810 01 Novoeight® in single-use vial [NDC 0169-7811-11] Pre-filled sodium chloride diluent in syringe, 4 mL [NDC 0169-7008-98] Vial adapter 1500 International Units NDC 0169 7815 01 Novoeight® in single-use vial [NDC 0169-7855-11] Pre-filled sodium chloride diluent in syringe, 4 mL [NDC 0169-7008-98] Vial adapter 2000 International Units NDC 0169 7820 01 Novoeight® in single-use vial [NDC 0169-7821-11] Pre-filled sodium chloride diluent in syringe, 4 mL [NDC 0169-7008-98] Vial adapter 3000 International Units NDC 0169 7830 01 Novoeight® in single-use vial [NDC 0169-7831-11] Pre-filled sodium chloride diluent in syringe, 4 mL [NDC 0169-7008-98] Vial adapter The Novoeight® vials are made of glass, closed with a chlorobutyl rubber stopper not made with natural rubber latex, and sealed with an aluminum cap. The pre-filled diluent syringes are made of glass, with a siliconised bromobutyl rubber plunger not made with natural rubber latex. The closed vials and pre-filled diluent syringes are equipped with a tamper-evident snap-off cap which is made of polypropylene. Storage And Handling Store Novoeight® in the original package in order to protect from light. Store Novoeight® under refrigeration at a temperature of 36°F–46°F (2°C – 8°C) for up to 30 months from the date of manufacture until the expiration date stated on the label. Within the 30-month period, Novoeight® may also be stored at room temperature not to exceed 86°F (30°C) for up to twelve (12) months. If you choose to store Novoeight® at room temperature, clearly record the date when the product was removed from the refrigerator in the space provided on the outer carton. The total time of storage at room temperature should not exceed 12 months. Do not return the product to the refrigerator. Do not use Novoeight® after the end of the 12-month period at room temperature storage, or after the expiration date stated on the vial, whichever occurs earlier. Do not freeze Novoeight®. Use Novoeight® within 4 hours after reconstitution when stored at room temperature. Store the reconstituted product in the vial. Discard any unused reconstituted product stored at room temperature for more than 4 hours. Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd, Denmark. Revised: Sep 2015

INDICATIONS KOVALTRY, Antihemophilic Factor (Recombinant), is a recombinant, human DNA sequence derived, full length Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital Factor VIII deficiency) for: On-demand treatment and cfont rol of bleeding episodes Perioperative management of bleeding Routine prophylaxis to reduce the frequency of bleeding episodes KOVALTRY is not indicated for the treatment of von Willebrand disease. DOSAGE AND ADMINISTRATION For intravenous use after reconstitution only. Dose Dosage and duration of treatment depend on the severity of the Factor VIII deficiency, the location and extent of bleeding, and the patient's clinical condition. Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes. Each vial label of KOVALTRY states the Factor VIII potency in international units (IU). One IU is defined by the current WHO (World Health Organization) international standard (IS) for Factor VIII concentrate. Potency assignment for KOVALTRY is determined using a chromogenic substrate assay. A field study involving 41 clinical laboratories from around the world measured recoveries of KOVALTRY spiked into hemophilic plasma. The results of the field study indicated that the Factor VIII activity of KOVALTRY can be accurately measured in plasma using either a one-stage clotting or chromogenic substrate assay according to routine methods of the testing laboratory. The required dose for a desired Factor VIII level expressed as IU/dL (or % of normal) can be estimated using the following formula: Required dose (IU) = body weight (kg) x desired Factor VIII rise (% of normal or IU/dL) x reciprocal of expected/observed recovery (e.g., 0.5 for a recovery of 2 IU/dL per IU/kg) The expected in vivo peak increase of Factor VIII level expressed as IU/dL (or % of normal) can be estimated using the following formula: Estimated increment of Factor VIII (IU/dL or % of normal) = [Total dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg) Examples (assuming patient's baseline Factor VIII is < 1%): A peak of 50% is required in a 20 kg child. In this situation, the required dose of KOVALTRY would be 20 kg x 50 IU/dL x 0.5% (for recovery of 2 IU/dL per IU/kg) = 500 IU A dose of 2000 IU of KOVALTRY administered to a 50 kg patient should be expected to result in post-infusion Factor VIII increase of 2000 IU / 50 kg (body weight) x 2 IU/dL per IU/kg = 80 IU/dL (80% of normal) Adjust dose to the patient's clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, incremental recovery) and clinical responses to KOVALTRY. On-Demand Treatment And Control Of Bleeding Episodes A guide for dosing KOVALTRY for the on-demand treatment and control of bleeding episodes is provided in Table 1. The goal of treatment is to maintain a plasma Factor VIII activity level at or above the plasma levels (in % of normal or in IU/dL) outlined in Table 1. Table 1: Dosing for Control of Bleeding Episodes Degree of Bleeding Factor VIII Level Required (IU/dL or % of normal) Frequency of Doses (hours) Duration of Therapy (days) Minor (Early hemarthrosis, minor muscle, oral bleeds) 20-40 Repeat every 12-24 hours At least 1 day, until bleeding episode as indicated by pain is resolved or healing is achieved Moderate (More extensive hemarthrosis, muscle bleeding, or hematoma) 30-60 Repeat every 12-24 hours 3 to 4 days or more until pain and acute disability are resolved Major (intracranial, intra-abdominal or intrathoracic hemorrhages, gastrointestinal bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath, life or limb threatening hemorrhage) 60-100 Repeat every 8-24 hours Until bleeding is resolved Perioperative Management Of Bleeding A guide for dosing KOVALTRY during surgery (perioperative management) is provided in Table 2. The goal of treatment is to maintain a plasma Factor VIII activity level at or above the plasma level (in % of normal or in IU/dL) outlined in Table 2. During major surgery, monitoring with appropriate laboratory tests, including serial Factor VIII activity assays, is highly recommended [see WARNINGS AND PRECAUTIONS]. Table 2: Dosing for Perioperative Management Type of Surgery Factor VIII Level Required (IU/dL or % of normal) Frequency of Doses (hours) Duration of Therapy (days) Minor (Such as tooth extraction) 30-60 (pre- and postoperative) Repeat every 24 hours At least 1 day until healing is achieved Major (Such as intracranial, intraabdominal, intrathoracic, or joint replacement surgery) 80-100 (pre- and postoperative) Repeat every 8-24 hours Until adequate wound healing is complete, then continue therapy for at least another 7 days to maintain Factor VIII activity of 30-60% (IU/dL) Routine Prophylaxis Individualize the patient's dose based on clinical response. Adults and adolescents: 20 to 40 IU of KOVALTRY per kg of body weight two or three times per week. Children ≤ 12 years old: 25 to 50 IU of KOVALTRY per kg body weight twice weekly, three times weekly, or every other day according to individual requirements [see Use in Specific Populations]. Preparation And Reconstitution Reconstitute and administer KOVALTRY with the components provided with each package. If any component of the package is opened or damaged, do not use this component. For any questions about the handling, reconstitution and administration of KOVALTRY, contact Bayer Medical Communications at 1-888-84-BAYER (1-888-842-2937). The procedures below are provided as general guidelines for the reconstitution of KOVALTRY using the sterile vial adapter with a 15 micrometer filter and a prefilled diluent syringe, which together serve as an alternative needleless reconstitution system. Usability Testing Of Vial Adapter Usability testing was conducted with 60 users, including 15 pediatric hemophilia A patients (between 10-17 years of age), 15 adult hemophilia A patients ( ≥ 18 years of age), 15 caregivers, and 15 healthcare providers. To mimic real life, the pediatric and adult patients and the caregivers were given minimal training, which included participants performing a supervised reconstitution and later performing a single unaided reconstitution. Healthcare providers were untrained in this study and could learn the procedure from the provided Instructions for Use. All participants were able to successfully and safely use the vial adapter device for reconstitution. Reconstitution Work on a clean surface and wash hands thoroughly using soap and warm water before performing the procedures. Reconstitute KOVALTRY with the components provided with each package. If any component of the package is opened or damaged, do not use this component. Filter the reconstituted product to remove potential particulate matter in the solution. Filtering is achieved by using the vial adapter. 1. Warm both unopened KOVALTRY vial and prefilled diluent syringe in your hands to a comfortable temperature (do not exceed 37°C or 99°F). 2. Remove the protective cap from the vial (A). Aseptically cleanse the rubber stopper with a sterile alcohol swab, being careful not to handle the rubber stopper. Figure A 3. Place the product vial on a firm, non-skid surface. Peel off the paper cover on the vial adapter plastic housing. Do not remove the adapter from the plastic housing. Holding the adapter housing, place over the product vial and firmly press down (B). The adapter will snap over the vial cap. Do not remove the adapter housing at this step. Figure B 4. Holding the syringe by the barrel, snap the syringe cap off the tip (C). Do not touch the syringe tip with your hand or any surface. Set the syringe aside for further use. Figure C 5. Now remove and discard the adapter plastic housing (D). Figure D 6. Attach the prefilled syringe to the vial adapter thread by turning clockwise (E). Figure E 7. Remove the clear plastic plunger rod from the carton. Grasp the plunger rod by the top plate. Avoid touching the sides and threads of the plunger rod. Attach the plunger rod by turning it clockwise into the threaded rubber stopper of the prefilled syringe (F). Figure F 8. Inject the diluent slowly by pushing down on the plunger rod (G). Figure G 9. Swirl vial gently until all powder on all sides of the vial is dissolved (H). Do not shake vial. Be sure that all powder is completely dissolved. Do not use if solution contains visible particles or is cloudy. Figure H 10. Push down on the plunger to push all air back into the vial. Then while holding the plunger down, turn the vial with syringe upside-down (invert) so the vial is now above the syringe (I). Figure I 11. Withdraw all the solution into the syringe by pulling the plunger rod back slowly and smoothly (J). Tilt the vial to the side and back to make sure all the solution has been drawn toward the large opening in the rubber stopper and into the syringe. Remove as much air as possible before removing the syringe from the vial by slowly and carefully pushing the air back into the vial. Figure J 12. Detach the syringe with plunger rod from the vial adapter by turning counter-clockwise. Attach the syringe to the administration set provided and inject intravenously (K). Note: follow instructions for infusion set provided. Figure K Pooling If the dose requires more than one vial, reconstitute each vial as described above with the diluent syringe provided. Use a larger plastic syringe (not provided) to combine the content of the vials into the syringe. Administration For intravenous use only. Inspect reconstituted KOVALTRY visually for particulate matter and discoloration prior to administration. Do not use if you notice any particulate matter or discoloration and immediately contact Bayer Medical Communications at 1-888-84-BAYER (1-888-842-2937). Administer reconstituted KOVALTRY as soon as possible. If not, store at room temperature for no longer than 3 hours. Infuse KOVALTRY intravenously over a period of 1 to 15 minutes. Adapt the rate of administration to the response of each individual patient. HOW SUPPLIED Dosage Forms And Strengths KOVALTRY is available as a lyophilized powder in single-use glass vials containing nominally 250, 500, 1000, 2000, or 3000 IU of recombinant Factor VIII per vial. Each vial of KOVALTRY is labeled with actual Factor VIII potency expressed in IU determined using a chromogenic substrate assay. This potency assignment employs a Factor VIII concentrate standard that is referenced to the current WHO International Standard for Factor VIII concentrate, and is evaluated by appropriate methodology to ensure accuracy of the results. KOVALTRY is available as a lyophilized powder in single-use glass vials, one vial per carton. It is supplied with a sterile vial adapter with 15-micrometer filter and a prefilled diluent glass barrel syringe, which together serve as a needleless reconstitution system. The prefilled diluent syringe contains Sterile Water for Injection, USP. An administration set is also provided in the package. Available sizes: Nominal Strength (IU) Diluent (mL) Kit NDC Number Color Code 250 2.5 0026-3821-25 Blue 500 2.5 0026-3822-25 Green 1000 2.5 0026-3824-25 Red 2000 5.0 0026-3826-50 Yellow 3000 5.0 0026-3828-50 Gray Actual Factor VIII activity in IU is stated on the label of each KOVALTRY vial. The product vial and diluent syringe are not made with natural rubber latex. Storage And Handling Product as Packaged for Sale Store KOVALTRY at +2°C to +8°C (36°F to 46°F) for up to 30 months from the date of manufacture. Do not freeze. Within this period, KOVALTRY may be stored for a single period of up to 12 months at temperatures up to +25°C or 77°F. Record the starting date of room temperature storage on the unopened product carton. Once stored at room temperature, do not return the product to the refrigerator. The shelf-life then expires after storage at room temperature for 12 months, or after the expiration date on the product vial, whichever is earlier. Do not use KOVALTRY after the expiration date indicated on the vial. Protect KOVALTRY from extreme exposure to light and store the vial with the lyophilized powder in the carton prior to use. Product After Reconstitution Administer reconstituted KOVALTRY as soon as possible. If not, store at room temperature for no longer than 3 hours. Do not use KOVALTRY if the reconstituted solution is cloudy or has particulate matter. Use the administration set provided. Bayer HealthCare LLC Whippany, NJ 07981 USA. Revised: Mar 2016

INDICATIONS The use of RECOMBINATE (antihemophilic factor (recombinant)) rAHF is indicated in hemophilia A (classical hemophilia) for the prevention and control of hemorrhagic episodes.1 RECOMBINATE (antihemophilic factor (recombinant)) rAHF is also indicated in the perioperative management of patients with hemophilia A (classical hemophilia). RECOMBINATE (antihemophilic factor (recombinant)) rAHF can be of therapeutic value in patients with acquired AHF inhibitors not exceeding 10 Bethesda Units per mL2. In clinical studies with RECOMBINATE (antihemophilic factor (recombinant)) rAHF, patients with inhibitors who were entered into the previously treated patient trial and those previously untreated children who have developed inhibitor activity on study, showed clinical hemostatic response when the titer of inhibitor was less than 10 Bethesda Units per mL. However, in such uses, the dosage of RECOMBINATE (antihemophilic factor (recombinant)) rAHF should be controlled by frequent laboratory determinations of circulating AHF levels. DOSAGE AND ADMINISTRATION Each bottle of RECOMBINATE (antihemophilic factor (recombinant)) rAHF is labeled with the AHF activity expressed in IU per bottle. This potency assignment is referenced to the World Health Organization International Standard for Factor VIII:C Concentrate and is evaluated by appropriate methodology to ensure accuracy of the results. The expected in vivo peak increase in AHF level expressed as IU/dL of plasma or % (percent) of normal can be estimated by multiplying the dose administered per kg body weight (IU/kg) by two. This calculation is based on the clinical findings of Abildgaard et al 8 and is supported by the data generated by 419 clinical pharmacokinetic studies with rAHF in 67 patients over time. This pharmacokinetic data demonstrated a peak recovery point above the pre- infusion baseline of approximately 2.0 IU/dL per IU/kg body weight. Example (Assuming patient's baseline AHF level is at < 1%): (1) A dose of 1750 IU AHF administered to a 70 kg patient, i.e. 25 IU/kg (1750/70), should be expected to cause a peak post-infusion AHF increase of 25 x 2 = 50 IU/dL (50% of normal). (2) A peak level of 70% is required in a 40 kg child. In this situation the dose would be 70/2 x 40 = 1400 IU. Recommended Dosage Schedule Physician supervision of the dosage is required. The following dosage schedule may be used as a guide. Hemorrhage Degree of hemorrhage Required peak post-infusion AHF activity in the blood (as % of normal or IU/dL plasma) Frequency of infusion Early hemarthrosis or muscle bleed or oral bleed 20-40 Begin infusion every 12 to 24 hours for one-three days until the bleeding episode as indicated by pain is resolved or healing is achieved. More extensive hemarthrosis, muscle bleed, or hematoma 30-60 Repeat infusion every 12 to 24 hours for usually three days or more until pain and disability are resolved. Life threatening bleeds such as head injury, throat bleed, severe abdominal pain 60-100 Repeat infusion every 8 to 24 hours until threat is resolved. Surgery Type of operation Minor surgery, including tooth extraction 60-80 A single infusion plus oral antifibrinolytic therapy within one hour is sufficient in approximately 70% of cases. Major surgery 80-100 (pre- and post-operative) Repeat infusion every 8 to 24 hours depending on state of healing. The careful control of the substitution therapy is especially important in cases of major surgery or life threatening hemorrhages. Although dosage can be estimated by the calculations above, it is strongly recommended that whenever possible, appropriate laboratory tests including serial AHF assays be performed on the patient's plasma at suitable intervals to assure that adequate AHF levels have been reached and are maintained. Other dosage regimens have been proposed such as that of Schimpf, et al, which describes continuous maintenance therapy.9 Reconstitution: Use Aseptic Technique Bring RECOMBINATE, Antihemophilic Factor (Recombinant) (rAHF) (dry concentrate) and Sterile Water for Injection, USP, (diluent) to room temperature. Remove caps from concentrate and diluent bottles. Cleanse stoppers with germicidal solution and allow to dry prior to use. Remove protective covering from one end of double-ended needle and insert exposed needle through the center of the stopper. Remove protective covering from other end of double-ended needle. Invert diluent bottle over the upright RECOMBINATE (antihemophilic factor (recombinant)) rAHF bottle, then rapidly insert free end of the needle through the RECOMBINATE (antihemophilic factor (recombinant)) rAHF bottle stopper at its center. The vacuum in the bottle will draw in the diluent. Disconnect the two bottles by removing needle from diluent bottle stopper, then remove needle from RECOMBINATE (antihemophilic factor (recombinant)) rAHF bottle. Swirl gently until all material is dissolved. Be sure that RECOMBINATE (antihemophilic factor (recombinant)) rAHF is completely dissolved, otherwise active material will be removed by the filter needle. NOTE: Do not refrigerate after reconstitution. See Administration. Administration: Use Aseptic Technique Administer at room temperature. RECOMBINATE (antihemophilic factor (recombinant)) rAHF should be administered not more than 3 hours after reconstitution. Intravenous Syringe Injection Parenteral drug products should be inspected for particulate matter and discoloration prior to administration, whenever solut ion and container permit. A colorless to faint yellow appearance is acceptable for RECOMBINATE (antihemophilic factor (recombinant)) rAHF. Plastic syringes are recommended for use with this product since proteins such as AHF tend to stick to the surface of all- glass syringes. Attach filter needle to a disposable syringe and draw back plunger to admit air into the syringe. Insert needle into reconstituted RECOMBINATE (antihemophilic factor (recombinant)) rAHF. Inject air into bottle and then withdraw the reconstituted material into the syringe. Remove and discard the filter needle from the syringe; attach a suitable needle and inject intravenously as instructed under Rate of Administration. If a patient is to receive more than one bottle of RECOMBINATE (antihemophilic factor (recombinant)) rAHF, the contents of multiple bottles may be drawn into the same syringe by drawing up each bottle through a separate unused filter needle. Filter needles are intended to filter the contents of a single bottle of RECOMBINATE (antihemophilic factor (recombinant)) rAHF only. Rate of Administration Preparations of RECOMBINATE, Antihemophilic Factor (Recombinant) (rAHF) can be administered at a rate of up to 10 mL per minute with no significant reactions. The pulse rate should be determined before and during administration of RECOMBINATE (antihemophilic factor (recombinant)) rAHF. Should a significant increase in pulse rate occur, reducing the rate of administration or temporarily halting the injection usually allows the symptoms to disappear promptly. HOW SUPPLIED RECOMBINATE (antihemophilic factor (recombinant)) rAHF is available in single-dose bottles which contain nominally 250, 500 and 1000 International Units per bottle. RECOMBINATE (antihemophilic factor (recombinant)) rAHF is packaged with 10 mL of Sterile Water for Injection, USP, a double-ended needle, a filter needle, one physician insert and one patient insert. Storage RECOMBINATE (antihemophilic factor (recombinant)) rAHF can be stored under refrigeration [2° - 8°C (36° - 46°F)] or at room temperature, not to exceed 30°C (86°F). Avoid freezing to prevent damage to the diluent bottle. Do not use beyond the expiration date printed on the box. REFERENCES 1. White GC, McMillan CW, Kingdon HS, et al: Use of recombinant antihemophilic factor in the treatment of two patients with classic hemophilia. New Eng J Med 320:166-170, 1989 2. Kessler CM: An Introduction to Factor VIII Inhibitors: The Detection and Quantitation. Am J Med 91 (Suppl 5A):1S-5S, 1991 8. Abildgaard CF, Simone JV, Corrigan JJ, et al: Treatment of hemophilia with glycine-precipitated Factor VIII. New Eng J Med 275:471-475, 1966 9. Schimpf K, Rothman P, Zimmermann K: Factor VIII dosis in prophylaxis of hemophilia A; A further controlled study in Proc XIth Cong W.F.H. Kyoto, Japan, Academic Press, 1976, pp 363-366 To enroll in the confidential, industry-wide Patient Notification System, call 1-888-UPDATE U (1-888-873-2838). Manufactured by: Baxter Healthcare Corporation Westlake Village, CA 91362, USA. Revised December 2004.

INDICATIONS Control And Prevention Of Bleeding Episodes Kogenate® FS is an antihemophilic factor that is indicated for the control and prevention of bleeding episodes in adults and children (0-16 years) with hemophilia A. Peri-operative Management Kogenate FS is indicated for surgical prophylaxis in adults and children with hemophilia A. Routine Prophylaxis In Children With Hemophilia A With No Pre-existing Joint Damage Kogenate FS is indicated for routine prophylactic treatment to reduce the frequency of bleeding episodes and the risk of joint damage in children with no pre-existing joint damage. Kogenate FS is not indicated for the treatment of von Willebrand's disease. DOSAGE AND ADMINISTRATION For Intravenous Use After Reconstitution Treatment with Kogenate FS should be initiated under the supervision of a physician experienced in the treatment of hemophilia A. Each vial of Kogenate FS has the recombinant factor VIII (rFVIII) potency in international units stated on the label. Dosage and duration of treatment depend on the severity of the factor VIII deficiency, the location and extent of bleeding, and the patient's clinical condition.1 Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes. [See Table 1 and Table 2.] The expected in vivo peak increase in factor VIII level expressed as IU/dL (or % normal) can be estimated using the following formulas: Dosage (units) = body weight (kg) x desired factor VIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL) OR IU/dL (or % normal)=Total Dose (IU)/body weight (kg) x 2 [IU/dL]/[IU/kg] Examples (assuming patient's baseline factor VIII level is < 1% of normal): A dose of 1750 IU Kogenate FS administered to a 70 kg patient should be expected to result in a peak post-infusion factor VIII increase of 1750 IU x {[2 IU/dL]/[IU/kg]}/[70 kg] = 50 IU/dL (50% of normal). A peak level of 50% is required in a 15 kg child. In this situation, the appropriate dose would be: 50 IU/dL/{[2 IU/dL]/[IU/kg]} x 15 kg = 375 IU. Doses administered should be titrated to the patient's clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to Kogenate FS.2,3,4 Although the dose can be estimated by the calculations above, it is highly recommended that, whenever possible, appropriate laboratory tests including serial factor VIII activity assays be performed. [See WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY] Control And Prevention Of Bleeding Episodes The careful control of treatment dose is especially important in cases of life-threatening bleeding episodes or major surgery. The following table can be used to guide dosing in bleeding episodes: Table 1 : Control and Prevention of Bleeding Episodes for Children and Adults Type of Bleeding Episode F actor VIII Level Required (IU/dL or % of normal) Dosage and Frequency Necessary to Maintain the Therapeutic Plasma Level Minor Early hemarthrosis, minor muscle or oral bleeds. 20-40 10-20 IUper kg Repeat dose if there is evidence of further bleeding. Moderate Bleeding into muscles, bleeding into the oral cavity, definite hemarthroses, and known trauma. 30-60 15-30 IUper kg Repeat dose every 12-24 hours until bleeding is resolved. Major Gastrointestinal bleeding. Intracranial, intra-abdominal or intrathoracic bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath. Fractures. Head trauma. 80-100 Initial dose 40-50 IU per kg Repeat dose 20-25 IU per kg every 8-12 hours until bleeding is resolved. Peri-Operative Management The careful control of treatment dose is especially important in cases of major surgery or life-threatening bleeding episodes. The following table can be used to guide dosing in surgery: Table 2 : Peri-operative Management for Adults and Children Type of Surgery F actor VIII Level Required (IU/dL or % of normal) Dosage and Frequency Necessary to Maintain the Therapeutic Plasma Level Minor Including tooth extraction 30-60 15-30 IUper kg Repeat dose every 12-24 hours until bleeding is resolved. Major Examples include tonsillectomy, inguinal herniotomy, synovectomy, total knee replacement, craniotomy, osteosynthesis, trauma. 100 Pre-operative dose 50 IU per kg Verify 100% activity prior to surgery. Repeat as necessary after 6 to 12 hours initially, and for 10 to 14 days until healing is complete. Routine Prophylaxis In Children With No Pre-existing Joint Damage The recommended dose for routine prophylaxis is 25 IU/kg of body weight every other day.5 Instructions For Use Kogenate FS is administered by intravenous (IV) injection after reconstitution. Patients should follow the specific reconstitution and administration procedures provided by their physicians. Kogenate FS should be reconstituted and administered with the components provided with each package. If any component of the package is opened or damaged, do not use this component. Product reconstitution, administration, and handling of the administration set and needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in a sharps container after single use. Discard all equipment, including any reconstituted Kogenate FS product, in an appropriate container. For any questions about the handling, reconstitution and administration of Kogenate FS, contact Bayer Medical Communications at 1-888-84-BAYER (1-888-842-2937). For instructions, patients should follow the recommendations in the FDA-Approved Patient Labeling. [See FDA Approved Patient Labeling] Preparation And Reconstitution The procedures below are provided as general guidelines for the reconstitution of Kogenate FS. Work on a clean surface and wash hands thoroughly using soap and warm water before performing the procedures. Reconstitute the product with the components provided with each package. If any component of the package is opened or damaged, do not use this component. Filter the reconstituted product to remove potential particulate matter in the solution. Filtering can be achieved by following the reconstitution steps as described below [see Administration]. Vacuum Transfer and Reconstitution Prepare the product under aseptic conditions. Warm the unopened diluent and the concentrate to a temperature not to exceed 37°C or 99°F. After removing the plastic flip-top caps (Fig. A), aseptically cleanse the rubber stoppers of both vials with alcohol, being careful not to handle the rubber stopper. Remove the protective cover from one end of the plastic transfer needle cartridge and penetrate the stopper of the diluent vial (Fig. B). Remove the remaining portion of the protective cover, invert the diluent vial and penetrate the rubber seal on the concentrate vial (Fig. C) with the needle at an angle. The vacuum will draw the diluent into the concentrate vial. Hold the diluent vial at an angle to the concentrate vial in order to direct the jet of diluent against the wall of the concentrate vial (Fig. C). Avoid excessive foaming. If the diluent does not get drawn into the vial, there is insufficient vacuum and the product should not be used. After removing the diluent vial and transfer needle (Fig. D), swirl until completely dissolved without creating excessive foaming (Fig. E). Re-swab top of reconstituted Kogenate FS vial with alcohol. Allow the stopper to air dry. After the concentrate powder is completely dissolved, withdraw the solution into the syringe through the filter needle that is supplied in the package (Fig. F). Replace the filter needle with the administration set provided and inject intravenously. If the same patient is to receive more than one vial, the contents of two vials may be drawn into the same syringe through a separate unused filter needle before attaching the vein needle. Figure A, B, C, D, E and F Administration For Intravenous Use Only After Reconstitution Inspect Kogenate FS visually for particulate matter and discoloration prior to administration, wherever solution and container permit. Do not use Kogenate FS if you notice any particulates or turbidity in the solution. Store the reconstituted Kogenate FS at room temperature prior to administration, but administer it within 3 hours. Administer Kogenate FS with the administration set provided with the product as it incorporates an in-line filter. In situations where the administration set provided cannot be used (e.g. when infusing into a peripheral or central line), use a separate filter compatible with Kogenate FS. NOTE: Do not use the administration set provided with the product to draw blood because it contains an in-line filter. When blood must be withdrawn prior to an infusion, use an administration set without a filter, then infuse Kogenate FS through an injection filter. For any questions about compatible separate filters, contact Bayer Medical Communications at 1-888-84-BAYER (1-888-842-2937). Administer Kogenate FS over a period of 1 to 15 minutes. Adapt the rate of administration to the response of each individual patient. Determine the pulse rate before and during administration of Kogenate FS. If there is a significant increase in pulse rate, reduce the rate of administration or temporarily halt the infusion allowing the symptoms to disappear promptly. HOW SUPPLIED Dosage Forms And Strengths Kogenate FS is available as a lyophilized powder in single use glass vials containing 250, 500, 1000, 2000, and 3000 International Units (IU). Each vial of Kogenate FS is labeled with the recombinant antihemophilic factor activity expressed in IU per vial. This potency assignment employs a factor VIII concentrate standard that is referenced to a WHO International Standard for factor VIII concentrates, and is evaluated by appropriate methodology to ensure accuracy of the results. Kogenate FS is available as a kit in the following single use glass vial sizes. A suitable volume of Sterile Water for Injection, USP, a double-ended transfer needle, a filter needle, and an administration set are provided in the kit. NDC Number Approximate FVIII Activity (IU) Diluent (mL) 0026-3782-20 250 2.5 0026-3783-30 500 2.5 0026-3785-50 1000 2.5 0026-3786-60 2000 5.0 0026-3787-70 3000 5.0 Actual factor VIII activity in IU is stated on the label of each Kogenate FS Vial. Storage And Handling Product as Packaged for Sale Store Kogenate FS at +2°C to +8°C (36°F to 46°F) for up to 30 months from the date of manufacture. Within this period, Kogenate FS may be stored for a period of up to 12 months at temperatures up to +25°C or 77°F, such as in home treatment situations. The starting date of room temperature storage should be clearly recorded on the unopened product carton. Once stored at room temperature, the product must not be returned to the refrigerator. The shelf-life then expires after the storage at room temperature, or the expiration date on the product vial, whichever is earlier. Do not use Kogenate FS after the expiration date indicated on the vial. Do not freeze. Protect from extreme exposure to light and store the lyophilized powder in the carton prior to use. Product After Reconstitution Administer Kogenate FS within 3 hours after reconstitution. It is recommended to use the administration set provided. REFERENCES 1. White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J, for the Factor VIII and Factor IX Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definitions in hemophilia. Thromb Haemost 85:560-75, 2001. 2. Abildgaard CF, Simone JV, Corrigan JJ, et al: Treatment of hemophilia with glycine-precipitated Factor VIII. N Engl J Med 275(9):471–5, 1966. 3. Schwartz RS, Abildgaard CF, Aledort LM, et al: Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. Recombinant Factor VIII Study Group. N Engl J Med 323(26):1800-5, 1990. 4. White GC 2nd, Courter S, Bray GL, et al: A multicenter study of recombinant factor VIII (Recombinate) in previously treated patients with hemophilia A. The Recombinate Previously Treated Patient Study Group. Thromb Haemost 77(4):660-667, 1997. 5. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007;357(6):535-44. Bayer HealthCare LLC, Tarrytown, NY 10591 USA. Revised: Jan 2013

INDICATIONS Helixate FS (antihemophilic factor (recombinant)) is indicated for the treatment of classical hemophilia (hemophilia A) in which there is a demonstrated deficiency of activity of the plasma clotting factor FVIII. Helixate FS (antihemophilic factor (recombinant)) provides a means of temporarily replacing the missing clotting factor in order to correct or prevent bleeding episodes, or in order to perform emergency or elective surgery in hemophiliacs. In clinical studies with the predecessor product HELIXATE, some patients who developed inhibitors on study continued to manifest a clinical response when inhibitor titers were less than 10 Bethesda Units (BU) per mL. When an inhibitor is present, the dosage requirement for FVIII is variable. The dosage can be determined only by clinical response, and by monitoring circulating FVIII levels after treatment (see DOSAGE AND ADMINISTRATION). Because Helixate FS (antihemophilic factor (recombinant)) has similar biological activity to HELIXATE it can be used in the same manner. Helixate FS (antihemophilic factor (recombinant)) does not contain von Willebrand's factor and therefore is not indicated for the treatment of von Willebrand's disease. DOSAGE AND ADMINISTRATION Each bottle of Helixate FS (antihemophilic factor (recombinant)) has the rFVIII potency in international units stated on the label based on the one-stage assay methodology. The reconstituted product must be administered within 3 hours after reconstitution. General Approach To Treatment And Assessment Of Treatment Efficacy The dosages described below are presented as general guidance. It should be emphasized that the dosage of Helixate FS (antihemophilic factor (recombinant)) required for hemostasis must be individualized according to the needs of the patient, the severity of the deficiency, the severity of the hemorrhage, the presence of inhibitors, and the FVIII level desired. It is often critical to follow the course of therapy with FVIII level assays. The clinical effect of FVIII is the most important element in evaluating the effectiveness of treatment. It may be necessary to administer more FVIII than estimated in order to attain satisfactory clinical results. If the calculated dose fails to attain the expected FVIII levels, or if bleeding is not controlled after administration of the calculated dosage, the presence of a circulating inhibitor in the patient should be suspected. Its presence should be substantiated and the inhibitor level quantitated by appropriate laboratory tests. When an inhibitor is present, the dosage requirement for FVIII could be extremely variable among different patients, and the optimal treatment can be determined only by the clinical response. Some patients with low-titer inhibitors ( < 10 BU) can be successfully treated with FVIII preparations without a resultant anamnestic rise in inhibitor titer.6 FVIII levels and clinical response to treatment must be assessed to insure adequate response. Use of alternative treatment products, such as Factor IX Complex concentrates, Antihemophilic Factor (Porcine), recombinant Factor VIIa or Anti-Inhibitor Coagulant Complex, may be necessary for patients with anamnestic responses to FVIII treatment and/or high-titer inhibitors. Calculation of Dosage The in vivo percent elevation in FVIII level can be estimated by multiplying the dose of Helixate FS (antihemophilic factor (recombinant)) per kilogram of body weight (IU/kg) by 2% per IU per kg. This method of calculation is based on clinical findings with the use of plasma-derived and recombinant AHF products7-9 and is illustrated in the following examples: Expected % factor VIII increase = # units administered x 2%/IU/kg body weight (kg) Example for a 70 kg adult: = 1400 IU x 2%/IU/kg = 40% 70 kg or Dosage required (IU) = body weight (kg) x desired % FVIII increase 2%/IU/kg Example for a 15 kg child: = 15 kg x 100% = 750 IU required 2%/IU/kg The dosage necessary to achieve hemostasis depends upon the type and severity of the bleeding episode, according to the following general guidelines: Hemorrhagic event Therapeutically necessary plasma level of FVIII activity Dosage necessary to maintain the therapeutic plasma level Minor hemorrhage (superficial, early hemorrhages, hemorrhages into joints) 20–40% 10–20 IU per kg Repeat dose if evidence of further bleeding. Moderate to major hemorrhage (hemorrhages into muscles, hemorrhages into the oral cavity, definite hemarthroses, known trauma) 30–60% 15–30 IU per kg Repeat one dose at 12–24 hours if needed. Surgery (minor surgical procedures) Major to life-threatening hemorrhage (intracranial, intraabdominal or intrathoracic hemorrhages, gastrointestinal bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath) 80–100% Initial dose 40–50 IU per kg Repeat dose 20–25 IU per kg every 8–12 hours. Fractures Head trauma Surgery Major surgical procedures ~100% Preoperative dose 50 IU/kg Verify ~100% activity prior to surgery. Repeat as necessary after 6 to 12 hours initially, and for 10 to 14 days until healing is complete. Prophylaxis AHF concentrates may also be administered on a regular schedule for prophylaxis of bleeding, as reported by Nilsson et al.10 Instructions for Use Reconstitution and product administration must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in a sharps container after single use. Discard all equipment, including any reconstituted Helixate® FS Antihemophilic Factor (Recombinant) product, in accordance with biohazard procedures. Reconstitution Always wash your hands before performing the following procedures: Vacuum Transfer Warm the unopened diluent and the concentrate to a temperature not to exceed 37°C, 99°F. Place the product vial, diluent vial and Mix2Vial™ on a flat surface. Ensure product and diluent vial flip caps are removed and the stoppers are treated with an aseptic solution and allowed to dry prior to opening the Mix2Vial package. Open the Mix2Vial package by peeling away the lid (Fig. 1). Leave the Mix2Vial in the clear package. Place the diluent vial on an even surface and hold the vial tight. Grip the Mix2Vial together with the package and snap the blue end onto the diluent stopper (Fig. 2). Carefully remove the clear package from the Mix2Vial set. Make sure that you only pull up the package and not the Mix2Vial set (Fig. 3). With the product vial firmly on a surface, invert the diluent vial with the set attached and snap the transparent adapter onto the product vial stopper (Fig. 4). The diluent will automatically transfer into the product vial. With the diluent and product vial still attached, gently swirl the product vial to ensure the product is fully dissolved (Fig. 5). Do not shake vial. With one hand grasp the product-side of the Mix2Vial set and with the other hand grasp the blue diluent-side of the Mix2Vial set and unscrew the set into two pieces (Fig. 6). Draw air into an empty, sterile syringe. While the product vial is upright, screw the syringe to the Mix2Vial set. Inject air into the product vial. While keeping the syringe plunger pressed, invert the system upside down and draw the concentrate into the syringe by pulling the plunger back slowly (Fig. 7). Now that the concentrate has been transferred into the syringe, firmly grasp the barrel of the syringe (keeping the syringe plunger facing down) and unscrew the syringe from the Mix2Vial set (Fig. 8). Attach the syringe to an administration set made with microbore tubing. Use of other administration sets without microbore tubing may result in a larger retention of the solution within the administration set. If the same patient is to receive more than one bottle, the contents of two bottles may be drawn into the same syringe through a separate unused Mix2Vial set before attaching the vein needle. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Rate of Administration The rate of administration should be adapted to the response of the individual patient, but administration of the entire dose in 5 to 10 minutes or less is well tolerated. HOW SUPPLIED Helixate® FS Antihemophilic Factor (Recombinant) is supplied in the following single use bottles. A suitable volume of Sterile Water for Injection, USP and Mix2Vial™ filter transfer set are provided. The actual potency is printed on the label and the carton. NDC Number Approximate FVIII Activity (IU) Dosage Diluent (mL) 0053-8130-01 250 LOW 2.5 0053-8130-02 500 MID 2.5 0053-8130-04 1000 HIGH 2.5 0053-8130-05 2000 ULTRAHIGH 5 Storage Helixate FS (antihemophilic factor (recombinant)) stored in a refrigerator at 2–8°C (36–46°F) is stable for the period indicated by the expiration date on the label. Within this period Helixate FS (antihemophilic factor (recombinant)) may be stored at room temperature, not to exceed 25°C (77°F), for up to 3 months, such as in home treatment situations. Do not freeze. Do not use beyond the expiration date indicated on the bottle. Protect from extreme exposure to light and store the lyophilized powder in the carton prior to use. REFERENCES 7. Abildgaard CF, Simone JV, Corrigan JJ, et al: Treatment of hemophilia with glycine-precipitated Factor VIII. N Engl J Med 275(9):471–5, 1966. 8. Schwartz RS, Abildgaard CF, Aledort LM, et al: Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. Recombinant Factor VIII Study Group. N Engl J Med 323(26):1800-5, 1990. 9. White GC 2nd, Courter S, Bray GL, et al: A multicenter study of recombinant factor VIII (Recombinate) in previously treated patients with hemophilia A. The Recombinate Previously Treated Patient Study Group. Thromb Haemost 77(4):660-667, 1997. 10. Nilsson IM, Berntorp E, Löfqvist T, et al: Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 232(1):25–32, 1992. Product Website: www.hemophiliamoms.com. Manufactured by: Bayer HealthCare LLC, Tarrytown, NY 10591, USA. Distributed by: CSL Behring LLC, Kankakee, IL 60901 USA. Revised July, 2007. FDA Rev date: July 2007

INDICATIONS Monoclate-P® is indicated for treatment of classical hemophilia (Hemophilia A). Affected individuals frequently require therapy following minor accidents. Surgery, when required in such individuals, must be preceded by temporary corrections of the clotting abnormality. Surgical prophylaxis in severe AHF deficiency can be accomplished with an appropriatelydosed pre-surgical IV bolus of Monoclate-P® followed by intermittent maintenance doses (see DOSAGE AND ADMINISTRATION). Monoclate-P® is not effective in controlling the bleeding of patients with von Willebrand's disease. DOSAGE AND ADMINISTRATION Monoclate-P® is for intravenous administration only. As a general rule 1 unit of AHF activity per kg will increase the circulating AHF level by 2%.10 The following formula10 provides a guide of dosage calculations for both adult and pediatric patients: Number of AHF I.U. Required = Body weight (in kg) x desired Factor VIII increase (% normal)x 0.5 Although dosage must be individualized according to the needs of the patient (weight, severity of hemorrhage, presence of inhibitors), the following general dosages are suggested.11 MILD HEMORRHAGES - Minor hemorrhagic episodes will generally subside with a single infusion if a level of 30% or more is attained. MODERATE HEMORRHAGE AND MINOR SURGERY - For more serious hemorrhages and minor surgical procedures, the patient's Factor VIII level should be raised to 30-50% of normal, which usually requires an initial dose of 15-25 I.U. per kg. If further therapy is required a maintenance dose is 10-15 I.U. per kg every 8-12 hours. SEVERE HEMORRHAGE - In hemorrhages near vital organs (neck, throat, subperitoneal) it may be desirable to raise the Factor VIII level to 80-100% of normal which can be achieved with an initial dose of 40-50 I.U. per kg and a maintenance dose of 20-25 I.U. per kg every 8-12 hours. MAJOR SURGERY - For surgical procedures a dose of AHF suffi cient to achieve a level 80-100% of normal should be given an hour prior to surgery. A second dose, half the size of the priming dose, should be given fi ve hours after the fi rst dose. Factor VIII levels should be maintained at a daily minimum of at least 30% for a period of 10-14 days postoperatively. Close laboratory control to maintain AHF plasma levels deemed appropriate to maintain hemostasis is recommended. Reconstitution Warm both the diluent and Monoclate-P® in unopened vials to room temperature [not above 37°C (98°F)]. Remove the caps from both vials to expose the central portions of the rubber stoppers. Treat the surface of the rubber stoppers with antiseptic solution and allow them to dry. Using aseptic technique, insert one end of the double-end needle into the rubber stopper of the diluent vial. Invert the diluent vial and insert the other end of the double-end needle into the rubber stopper of the Monoclate-P® vial. Direct the diluent, which will be drawn in by vacuum, over the entire surface of the Monoclate-P® cake. (In order to assure transfer of all the diluent, adjust the position of the tip of the needle in the diluent vial to the inside edge of the diluent stopper.) Rotate the vial to ensure complete wetting of the cake during the transfer process. Remove the diluent vial to release the vacuum, then remove the double-end needle, from the Monoclate-P® vial. Gently swirl the vial until the powder is dissolved and the solution is ready for administration. The concentrate routinely and easily reconstitutes within one minute. To assure sterility, Monoclate-P® should be administered within three hours after reconstitution. Parenteral drug preparations should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Administration CAUTION: This kit contains two devices, a stainless steel 5 micron filter needle, individually labeled as a 5 micron filter needle and contained in a separate blister pack, and an all plastic 5 micron vented filter spike which is supplied with the four-item administration components blister pack, either of which may be used to withdraw the reconstituted product for administration. The withdrawal directions specific for each of these alternate devices must be followed exactly for whichever device is chosen for use as described below. Product loss or inability to withdraw product will result if the improper instructions are followed. A. Administration using the stainless steel filter needle for withdrawal (This item is individually packaged in a separate, labeled blister pack.) Intravenous Injection Plastic disposable syringes are recommended with Monoclate-P® solution. The ground glass surfaces of all-glass syringes tend to stick with solutions of this type. Using aseptic technique, attach the filter needle to a sterile disposable syringe. Draw air into the syringe equal to or greater than the contents of the vial. Insert the filter needle into the stopper of the Monoclate-P® vial, invert the vial, position the filter needle above the level of the liquid and inject all of the air into the vial. Pull the filter needle back down below the level of the liquid until the tip is at the inside edge of the stopper. Withdraw the reconstituted solution into the syringe being careful to always keep the tip of the needle below the level of the liquid. CAUTION: Failure to inject air into the vial, or allowing air to pass through the filter needle while filling the syringe with reconstituted solution, may cause the needle to clog. Discard the filter needle. Perform venipuncture using the enclosed winged needle with microbore tubing. Attach the syringe to the luer end of the tubing. CAUTION: Use of other winged needles without microbore tubing, although compatible with the concentrate, will result in a larger retention of solution within the winged infusion set. Administer solution intravenously at a rate (approximately 2 mL/minute) comfortable to the patient. B. Administration using the all plastic vented fi lter spike for withdrawal (This spike is supplied in the four-item Administration Components pack.) Intravenous Injection Plastic disposable syringes are recommended with Monoclate-P® solution. The ground glass surfaces of all-glass syringes tend to stick with solutions of this type. Using aseptic technique, attach the vented filter spike to a sterile disposable syringe. CAUTION: DO NOT INJECT AIR INTO THE MONOCLATE-P® VIAL. The self-venting feature of the vented filter spike precludes the need to inject air in order to facilitate withdrawal of the reconstituted solution. The injection of air could cause partial product loss through the vent filter. CAUTION: The use of other, non-vented filter needles or spikes without the proper procedure may result in an air lock and prevent the complete transfer of the concentrate. Insert the vented filter spike into the stopper of the Monoclate-P® vial, invert the vial, and position the filter spike so that the orifice is at the inside edge of the stopper. Withdraw the reconstituted solution into the syringe. Discard the filter spike. Perform venipuncture using the enclosed winged needle with microbore tubing. Attach the syringe to the luer end of the tubing. CAUTION: Use of other winged needles without microbore tubing, although compatible with the concentrate, will result in a larger retention of solution within the winged infusion set. Administer solution intravenously at a rate (approximately 2 mL/minute) comfortable to the patient. Storage When stored at refrigerator temperature, 2-8°C (36-46°F), Monoclate-P® is stable for the period indicated by the expiration date on its label. Within this period, Monoclate-P® may be stored at room temperature not to exceed 25°C (77°F), for up to 6 months. Avoid freezing which may damage container for the diluent. HOW SUPPLIED Monoclate-P® is supplied in a single dose vial with Sterile Water for Injection, USP, double-ended needle for reconstitution, vented filter spike for withdrawal, filter needle for withdrawal, winged infusion set and alcohol swabs. Factor VIII activity in IU is stated on the label of each vial. Each product package consists of the following: NDC Number Approximate FVIII Activity (IU) Component 0053-7631-02 250 (LOW) Carton (kit) containing one vial of Monoclate-P® [NDC 0053-7641-01], one 2.5 mL vial of Sterile Water for Injection, USP (diluent) [NDC 0053-7653-02], one double-ended needle for reconstitution, one vented filter spike for withdrawal, one filter needle for withdrawal, one winged infusion set, and alcohol swabs. 0053-7632-02 500 (MID) Carton (kit) containing one vial of Monoclate-P® [NDC 0053-7642-01], one 5 mL vial of Sterile Water for Injection, USP (diluent) [NDC 0053-7653-05], one double-ended needle for reconstitution, one vented filter spike for withdrawal, one filter needle for withdrawal, one winged infusion set, and alcohol swabs. 0053-7633-02 1000 (HIGH) Carton (kit) containing one vial of Monoclate-P® [NDC 0053-7643-01], one 10 mL vial of Sterile Water for Injection, USP (diluent) [NDC 0053-7653-10], one double-ended needle for reconstitution, one vented filter spike for withdrawal, one filter needle for withdrawal, one winged infusion set, and alcohol swabs. 0053-7634-02 1500 (SUPER HIGH) Carton (kit) containing one vial of Monoclate-P® [NDC 0053-7644-01], one 10 mL vial of Sterile Water for Injection, USP (diluent) [NDC 0053-7653-10], one double-ended needle for reconstitution, one vented filter spike for withdrawal, one filter needle for withdrawal, one winged infusion set, and alcohol swabs. Bibliography Hershman, R.J., Naconti, S.B., and Shulman, N.R. Prophylactic Treatment of Factor VIII Defi ciency. Blood 35, (1970), p. 189. Kasper, C.K. Dietrich, S.I. and Rapaport, S.K. Hemophilia Prophylaxis in Factor VIII Concentrate. Arch Int Med 125, (1970), p. 1004. Biggs, R. ed. The Treatment of Hemophilia A and B and von Willebrands Disease. Oxford: Blackwell, 1978. Fulcher, C.A., Zimmerman, T.S., Characterization of the Human Factor VIII Procoagulant Protein With A Heterologous Precipitating Antibody. Proc Natl Acad Sci 79 (1982), pp. 1648-1652. Levine, P.H., Factor VIII C Purifi ed from Plasma Via Monoclonal Antibodies Human Studies. Semin Hematol 25 (2 Suppl. 1), 1988, pp. 38-41. REFERENCES 10. C.F. Abilgaard, J.V. Simone, J.J. Corrigan, et al., Treatment of Hemophilia with Glycine - Precipitated Factor VIII, New Eng J Med, 275 (1966), p. 471. 11. C.K. Kasper, Hematologic Care, Comprehensive Management of Hemophilia, ed. Boone, D.C., Philadelphia, F.A. Davis Co., (1976) pp. 2-20. Manufactured by: CSL Behring LLC, Kankakee, IL 60901 USA, US License No. 1767. Revised: Feb, 2014

INDICATIONS Koate (antihemophilic factor) -DVI is indicated for the treatment of classical hemophilia (hemophilia A) in which there is a demonstrated deficiency of activity of the plasma clotting factor, factor VIII. Koate (antihemophilic factor) -DVI provides a means of temporarily replacing the missing clotting factor in order to control or prevent bleeding episodes, or in order to perform emergency and elective surgery on individuals with hemophilia. Koate (antihemophilic factor) -DVI contains naturally occurring von Willebrand's factor, which is co-purified as part of the manufacturing process. Koate (antihemophilic factor) -DVI has not been investigated for efficacy in the treatment of von Willebrand's disease, and hence is not approved for such usage. DOSAGE AND ADMINISTRATION Each bottle of Koate (antihemophilic factor) -DVI has the AHF(H) content in international units per bottle stated on the label of the bottle. The reconstituted product must be administered intravenously by either direct syringe injection or drip infusion. The product must be administered within 3 hours after reconstitution. General Approach to Treatment and Assessment of Treatment Efficacy The dosages described below are presented as general guidance. It should be emphasized that the dosage of Koate (antihemophilic factor) -DVI required for hemostasis must be individualized according to the needs of the patient, the severity of the deficiency, the severity of the hemorrhage, the presence of inhibitors, and the factor VIII level desired. It is often critical to follow the course of therapy with factor VIII level assays. The clinical effect of Koate (antihemophilic factor) -DVI is the most important element in evaluating the effectiveness of treatment. It may be necessary to administer more Koate (antihemophilic factor) -DVI than would be estimated in order to attain satisfactory clinical results. If the calculated dose fails to attain the expected factor VIII levels, or if bleeding is not controlled after administration of the calculated dosage, the presence of a circulating inhibitor in the patient should be suspected. Its presence should be substantiated and the inhibitor level quantitated by appropriate laboratory tests. When an inhibitor is present, the dosage requirement for AHF(H) is extremely variable and the dosage can be determined only by the clinical response. Some patients with low titer inhibitors, (10 Bethesda Units) can be successfully treated with factor VIII without a resultant anamnestic rise in inhibitor titer.12 Factor VIII levels and clinical response to treatment must be assessed to insure adequate response. Use of alternative treatment products, such as Factor IX Complex concentrates, Antihemophilic Factor (Porcine) or Anti-Inhibitor Coagulant Complex, may be necessary for patients with high titer inhibitors. Immune tolerance therapy using repeated doses of FVIII concentrate administered frequently on a predetermined schedule may result in eradication of the FVIII inhibitor.13,14 Most successful regimens have employed high doses of FVIII administered at least once daily, but no single dosage regimen has been universally accepted as the most effective. Consultation with a hemophilia expert experienced with the management of immune tolerance regimens is also advisable. Calculation of Dosage The in vivo percent elevation in factor VIII level can be estimated by multiplying the dose of AHF(H) per kilogram of body weight (IU/kg) by 2%. This method of calculation is based on clinical findings by Abildgaard et al,15 and is illustrated in the following examples: Expected % factor VIII increase = # units administered X 2%/IU/kg body weight (kg) Example for a 70 kg adult: 1400 IU X 2%/IU/kg = 40% 70kg or Dosage required (IU) = body weight (kg) X desired % factor VIII increase 2%/IU/kg Example for a 15 kg child: 15 kg X 100% = 750 IU required 2%/IU/kg The dosage necessary to achieve hemostasis depends upon the type and severity of the bleeding episode, according to the following general guidelines: Mild Hemorrhage Mild superficial or early hemorrhages may respond to a single dose of 10 IU per kg,4 leading to an in vivo rise of approximately 20% in the factor VIII level. Therapy need not be repeated unless there is evidence of further bleeding. Moderate Hemorrhage For more serious bleeding episodes (e.g., definite hemarthroses, known trauma), the factor VIII level should be raised to 30%–50% by administering approximately 15 - 25 IU per kg. If further therapy is required, repeated doses of 10 - 15 IU per kg every 8-12 hours may be given.16 Severe Hemorrhage In patients with life-threatening bleeding or possible hemorrhage involving vital structures (e.g., central nervous system, retropharyngeal and retroperitoneal spaces, iliopsoas sheath), the factor VIII level should be raised to 80% - 100% of normal in order to achieve hemostasis. This may be achieved in most patients with an initial AHF [Antihemophilic Factor (Human), Koate (antihemophilic factor) w-DVI] dose of 40-50 IU per kg and a maintenance dose of 20-25 IU per kg every 8-12 hours.17,18 For major surgical procedures, Factor VIII levels should be checked throughout the perioperative course to ensure adequate replacement therapy. Surgery For major surgical procedures, the factor VIII level should be raised to approximately 100% by giving a preoperative dose of 50 IU/kg. The factor VIII level should be checked to assure that the expected level is achieved before the patient goes to surgery. In order to maintain hemostatic levels, repeat infusions may be necessary every 6 to 12 hours initially, and for a total of 10 to 14 days until healing is complete. The intensity of factor VIII replacement therapy required depends on the type of surgery and postoperative regimen employed. For minor surgical procedures, less intensive treatment schedules may provide adequate hemostasis.17,18 Prophylaxis Factor VIII concentrates may also be administered on a regular schedule for prophylaxis of bleeding, as reported by Nilsson et al.19 Incorrect diagnosis, inappropriate dosage, method of administration, and biological differences in individual patients, could reduce the efficacy of this product or even result in an ill effect following its use. It is important that this product be stored properly, the directions for use be followed carefully during use, the risk of transmitting viruses be carefully weighed before the product is prescribed, and that plasma factor VIII levels be measured in initial treatment situations or if clinical response appears inadequate. Reconstitution Vacuum Transfer Note: Aseptic technique should be carefully followed. All needles and vial tops that will come into contact with the product to be administered via the intravenous route should not come in contact with any non-sterile surface. Any contaminated needles should be discarded by placing in a puncture proof container, and new equipment should be used. After removing all items from the box, warm the sterile water (diluent) to room temperature (25°C, 77°F). Remove shrink band from product vial. If the shrink band is absent or shows signs of tampering, do not use the product and notify Talecris Biotherapeutics, Inc. immediately. Remove the plastic flip tops from each vial (Fig. A). Cleanse vial tops (grey stoppers) with alcohol swab and allow surface to dry. After cleaning, do not allow anything to touch the latex (rubber) stopper. Carefully remove the plastic sheath from the short end of the transfer needle. Insert the exposed needle into the diluent vial to the hub. (Fig. B) Carefully grip the sheath of the other end of the transfer needle and twist to remove it. Invert the diluent vial and insert the attached needle into the vial of concentrate at a 45° angle (Fig. C). This will direct the stream of diluent against the wall of the concentrate vial and minimize foaming. The vacuum will draw the diluent into the concentrate vial. ** Remove the diluent bottle and transfer needle (Fig. D). Immediately after adding the diluent, agitate vigorously for 10–15 seconds, (Fig. E1) then swirl continuously until completely dissolved (Fig. E2). Some foaming will occur, but attempt to avoid excessive foaming. The vial should then be visually inspected for particulate matter and discoloration prior to administration. Clean the top of the vial of reconstituted Koate (antihemophilic factor) -DVI again with alcohol swab and let surface dry. Attach the filter needle (from the package) to a sterile syringe. Withdraw the Koate (antihemophilic factor) -DVI solution into the syringe through the filter needle (Fig. F). Remove the filter needle from the syringe and replace with an appropriate injection or butterfly needle for administration. Discard filter needle into a puncture proof container. If the same patient is using more than one vial of Koate (antihemophilic factor) -DVI, the contents of multiple vials may be drawn into the same syringe through the filter needles provided. **If vacuum is lost in the concentrate vial, use a sterile syringe and needle to remove the sterile water from the diluent vial and inject it into the concentrate vial, directing the stream of fluid against the wall of the vial. A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include improper storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration, and biological differences in individual patients. Because of these factors, it is important that this product be stored properly, that the directions be followed carefully during use, and that the risk of transmitting viruses be carefully weighed before the product is prescribed. Rate of Administration The rate of administration should be adapted to the response of the individual patient, but administration of the entire dose in 5 to 10 minutes is generally well-tolerated. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. HOW SUPPLIED Koate (antihemophilic factor) -DVI is supplied in the following single dose bottles with the total units of factor VIII activity stated on the label of each bottle. A suitable volume of Sterile Water for Injection, USP, a sterile double-ended transfer needle, a sterile filter needle, and a sterile administration set are provided. Approximate Factor VIII NDC Number Activity Diluent 13533-665-20 250 IU 5 mL 13533-665-30 500 IU 5 mL 13533-665-50 1000 IU 10 mL Storage Koate (antihemophilic factor) -DVI should be stored under refrigeration (2–8°C; 36–46°F). Storage of lyophilized powder at room temperature (up to 25°C or 77°F) for 6 months, such as in home treatment situations, may be done without loss of factor VIII activity. Freezing should be avoided as breakage of the diluent bottle might occur. REFERENCES 4. Britton M, Harrison J, Abildgaard CF: Early treatment of hemophilic hemarthroses with minimal dose of new factor VIII concentrate. J Pediatr 85(2):245–7, 1974. 12. Kasper CK: Complications of hemophilia A treatment: factor VIII inhibitors. Ann NY Acad Sci 614:97–105, 1991. 13. Mariani G, Hilgartner M, Thompson AR, et al: Immune Tolerance to Factor VIII: International Registry Data. Adv Exp Med Biol 386:201–8, 1995. 14. DiMichele D: Hemophilia 1996, New Approach to an Old Disease. Pediatr Clin North Am 43(3):709–35, Jun 1995. 15. Abildgaard CF, Simone JV, Corrigan JJ, et al: Treatment of hemophilia with glycine-precipitated factor VIII. N Engl J Med 275(9):471–5, 1966. 16. Abildgaard CF: Current concepts in the management of hemophilia. Semin Hematol 12(3):223–32, 1975. 17. Hilgartner MW: Factor replacement therapy. In: Hilgartner MW, Pochedly C, eds.: Hemophilia in the child and adult. New York, Raven Press, 1989, pp 1–26. 18. Kasper CK, Dietrich SL: Comprehensive management of haemophilia. Clin Haematol 14(2):489–512, 1985. 19. Nilsson IM, Berntorp E, Löfqvist T, et al: Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 232(1):25–32, 1992. Talecris Biotherapeutics, Inc., Research Triangle Park, NC 27709 USA. Rev. September 2006.

INDICATIONS ALPHANATE, (antihemophilic factor/von Willebrand factor complex [human]), is indicated for: Control and prevention of bleeding episodes and perioperative management in adult and pediatric patients with Factor VIII (FVIII) deficiency due to hemophilia A. Surgical and/or invasive procedures in adult and pediatric patients with von Willebrand Disease (VWD) in whom desmopressin (DDAVP) is either ineffective or contraindicated. It is not indicated for patients with severe VWD (Type 3) undergoing major surgery. DOSAGE AND ADMINISTRATION For intravenous injection after reconstitution only Treatment with ALPHANATE should be initiated under the supervision of a physician experienced in the treatment of hemophilia. Each vial of ALPHANATE has the antihemophilic factor (AHF) potency (FVIII:C activity) expressed in International Units (IU) FVIII/vial on the label. Additionally, ALPHANATE contains von Willebrand Factor:Ristocetin Cofactor (VWF:RCo), which is expressed in IU VWF:RCo/vial for the treatment of VWD. Dose Treatment And Prevention Of Bleeding Episodes And Excess Bleeding During And After Surgery In Patients with Hemophilia A Dosage and duration of treatment depend on the severity of the FVIII deficiency, the location and extent of bleeding, presence of inhibitors, and the patient's clinical condition. Careful control of replacement therapy is especially important in cases of major surgery or lifethreatening bleeding episodes. Dosing requirements and frequency of dosing is calculated on the basis of an expected initial response of 2% of normal FVIII:C increase per IU FVIII:C/kg body weight administered.1 The expected in vivo peak increase in FVIII level expressed as IU/dL (or % of normal) can be estimated using the following formulas: Dosage (international units) = body weight (kg) x desired FVIII rise (IU/dL or % normal) x 0.5 (IU/kg per IU/dL) or IU/dL (or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 Titrate dose and frequency to the patient's clinical response, including individualized needs, severity of the deficiency, severity of the hemorrhage, presence of inhibitors, and FVIII level desired. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to ALPHANATE. Table 1 provides dosage guidelines for the control and prevention of bleeding episodes in hemophilia A patients. Dosing should aim at maintaining a plasma factor VIII activity level at or above the plasma levels (in IU/dL or in % of normal) outlined in the table. Table 1: Dosage Guidelines for Patients with Hemophilia A Type of Bleeding FVIII:C Level Required (% of normal) Doses (IU/kg) Frequency of Doses (hours) Duration of Therapy (days) Minor Large bruises Significant cuts or scrapes Uncomplicated joint hemorrhage 30 15 12 (twice daily) Until hemorrhage stops and healing has been achieved (1-2 days). Moderate Nose, mouth and gum bleeds Dental extractions Hematuria 50 25 12 (twice daily) Until healing has been achieved (2-7 days, on average). Major Joint hemorrhage Muscle hemorrhage Major trauma Hematuria Intracranial and intraperitoneal bleeding 80-100 Initial: 40-50 Maintenance: 25 12 (twice daily) For at least 3-5 days Until healing has been achieved for up to 10 days. Intracranial hemorrhage may require prophylaxis therapy for up to 6 months. Surgery Prior to surgery: 80-100 After surgery: 60-100 40-50 30-50 Once 12 (twice daily) Prior to surgery For the next 7-10 days, or until healing has been achieved. Monitoring parameters: Monitor plasma FVIII levels periodically to evaluate individual patient response to the dosage regimen. If dosing studies have determined that a particular patient exhibits a lower/higher than expected response and shorter/longer half-life, adjust the dose and the frequency of dosing accordingly. Failure to achieve the expected plasma FVIII:C level or to control bleeding after an appropriately calculated dosage may be indicative of the development of an inhibitor (an antibody to FVIII:C). Quantitate the inhibitor level by appropriate laboratory procedures and document its presence. Treatment with AHF in such cases must be individualized.2 Treatment And Prevention Of Excess Bleeding During And After Surgery Or Other Invasive Procedures In Patients With Von Willebrand Disease The ratio of VWF:RCo to FVIII in ALPHANATE varies by lot, so with each new lot, check IU VWF:RCo/vial to ensure accurate dosing. Dosage and duration of treatment depend on the severity of the VWF deficiency, the location and extent of bleeding, and the patient's clinical condition. Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes. The median incremental in vivo recoveries of VWF:RCo and FVIII:C were 3.12 (IU/dL)/(IU/kg) [mean, 3.29 ± 1.46 (IU/dL)/(IU/kg); range: 1.28 to 5.73 (IU/dL)/(IU/kg)] for VWF:RCo and 1.95 (IU/dL)/(IU/kg) [mean, 2.13 ± 0.58 (IU/dL)/(IU/kg); range: 1.33 to 3.32 (IU/dL)/(IU/kg)] for FVIII:C. Table 2 provides dosing guidelines for pediatric and adult patients with von Willebrand Disease.3-6 Table 2: Dosage Guidelines for Patients with von Willebrand Disease (Except Type 3 Subjects Undergoing Major Surgery) Minor Surgery/Bleeding Parameter VWF:RCo Target FVIII:C Activity Levels Pre-operative/pre-procedure dose: Adults: 60 IU VWF:RCo/kg body weight. Pediatrics: 75 IU VWF:RCo/kg body weight. 40-50 IU/dL Maintenance dose: Adults: 40 to 60 IU VWF:RCo/kg body weight at 8 to 12 hour intervals as clinically needed for 1-3 days. Pediatrics: 50 to 75 IU VWF:RCo/kg body weight at 8 to 12 hour intervals as clinically needed for 1-3 days. 40-50 IU/dL Therapeutic Goal (Trough)a: > 50 IU/dL > 50 IU/dL Safety Monitoring: Peak and trough at least once daily Peak and trough at least once daily Safety Parameterb: Should not exceed 150 IU/dL Should not exceed 150 IU/dL Major Surgery/Bleeding Parameter VWF:RCo Target FVIII:C Activity Levels Pre-operative/pre-procedure dose: Adults: 60 IU VWF:RCo/kg body weight. Pediatrics: 75 IU VWF:RCo/kg body weight. 100 IU/dL Maintenance dose: Adults: 40 to 60 IU VWF:RCo/kg body weight at 8 to 12 hour intervals as clinically needed for at least 3-7 days. Pediatrics: 50 to 75 IU VWF:RCo/kg body weight at 8 to 12 hour intervals as clinically needed for at least 3-7 days. 100 IU/dL Therapeutic Goal (Trough)a: > 50 IU/dL > 50 IU/dL Safety Monitoring: Peak and trough at least daily Peak and trough at least daily Safety Parameterb: Should not exceed 150 IU/dL Should not exceed 150 IU/dL a The therapeutic goal is referenced in the NHLBI Guidelines.7 b The safety parameter is extracted from Mannucci 2009.8 Reconstitution Always use aseptic technique. Ensure that concentrate (ALPHANATE) and diluent (Sterile Water for Injection, USP) are at room temperature (but not above 37 °C) before reconstitution. Remove the plastic flip off cap from the diluent vial. Gently swab the exposed stopper surface with a cleansing agent such as alcohol trying to avoid leaving any excess cleansing agent on the stopper. Open the Mix2Vial package by peeling away the lid (Figure 1). Leave the Mix2Vial in the clear outer packaging. Place the diluent vial upright on an even surface and hold the vial tight and pick up the Mix2Vial in its clear outer packaging. Holding the diluent vial securely, push the blue end of the Mix2Vial vertically down through the diluent vial stopper (Figure 2). While holding onto the diluent vial, carefully remove the clear outer packaging from the Mix2Vial set, ensuring the Mix2Vial remains attached to the diluent vial (Figure 3). Place the product vial upright on an even surface, invert the diluent vial with the Mix2Vial attached. Figure 1,  2, 3, 4 , 5, 6 , 7and 8 While holding the product vial securely on a flat surface, push the clear end of the Mix2Vial set vertically down through the product vial stopper (Figure 4). The diluent will automatically transfer out of its vial into the product vial. NOTE: If the Mix2Vial is connected at an angle, the vacuum may be released from the product vial and the diluent will not transfer into the product vial. With the diluent and product vials still attached to the Mix2Vial, gently swirl the product vial to ensure the product is fully dissolved (Figure 5). Reconstitution requires less than 5 minutes. Do not shake the vial. Disconnect the Mix2Vial into two separate pieces (Figure 6) by holding each vial adapter and twisting counterclockwise. After separating, discard the diluent vial with the blue end of the Mix2Vial. Draw air into an empty, sterile syringe. Keeping the product vial upright with the clear end of the Mix2Vial attached, screw the disposable syringe onto the luer lock portion of the Mix2Vial device by pressing and twisting clockwise. Inject air into the product vial. While keeping the syringe plunger depressed, invert the system upside down and draw the reconstituted product into the syringe by pulling the plunger back slowly (Figure 7). When the reconstituted product has been transferred into the syringe, firmly hold the barrel of the syringe and the clear vial adapter (keeping the syringe plunger facing down) and unscrew the syringe from the Mix2Vial (Figure 8). Hold the syringe upright and push the plunger until no air is left in the syringe. Attach the syringe to a venipuncture set. NOTE: If the same patient is to receive more than one vial of concentrate, the contents of two vials may be drawn into the same syringe through a separate unused Mix2Vial set before attaching to the venipuncture set. When reconstitution procedure is strictly followed, a few small particles may occasionally remain. The Mix2Vial set will remove particles and the labeled potency will not be reduced. Discard all reconstitution equipment after use into the appropriate safety container. Do not reuse. Use the prepared drug as soon as possible within 3 hours after reconstitution. Administration For intravenous use after reconstitution only Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not refrigerate after reconstitution. Store reconstituted ALPHANATE at room temperature (not to exceed 30 °C) prior to administration, but administer intravenously within three hours. Use plastic disposable syringes. Do not administer ALPHANATE at a rate exceeding 10 mL/minute. Discard any unused contents into the appropriate safety container. HOW SUPPLIED Dosage Forms And Strengths ALPHANATE is available as a lyophilized powder for intravenous injection after reconstitution. It is available in the following potencies: 250 IU FVIII/5 mL single dose vial 500 IU FVIII/5 mL single dose vial 1000 IU FVIII/10 mL single dose vial 1500 IU FVIII/10 mL single dose vial 2000 IU FVIII/10 mL single dose vial ALPHANATE is supplied in sterile, lyophilized form in a single dose vial with a vial of diluents (Sterile Water for Injection, USP) and a Mix2Vial filter transfer set. IU activity of FVIII and VWF:RCo are stated on the carton and label of each vial. ALPHANATE is available in the following potencies and color coded based upon assay on the carton and label as follows: Potency NDC Assay Color Code 250 IU FVIII/5 mL single dose vial 68516-4601-1 250 IU FVIII Range - grey box 500 IU FVIII/5 mL single dose vial 68516-4602-1 500 IU FVIII Range - blue box 1000 IU FVIII/10 mL single dose vial 68516-4603-2 1000 IU FVIII Range - red box 1500 IU FVIII/10 mL single dose vial 68516-4604-2 1500 IU FVIII Range - black box 2000 IU FVIII/10 mL single dose vial 68516-4609-2 2000 IU FVIII Range - green box Storage And Handling ALPHANATE is stable for three years, up to the expiration date printed on its label, provided that the storage temperature does not exceed 25 °C (77 °F). Do not freeze. REFERENCES 1. Srivastava, A., Brewer, A.K., et al. WFH Guidelines: Guidelines for the management of hemophilia. Haemophilia 2013; 19, e1-e47. 2. Kempton, C.L., White, G.C. How we treat a hemophilia A patient with a factor VIII inhibitor. Blood 2009; 113:11-17. 3. Federici, A.B., Baudo, F., Caracciolo, C., Mancuso, G., Mazzucconi, M.G., Musso, R., Schinco, P.C., Targhetta. R., Mannucci, P.M. Clinical efficacy of highly purified, doubly virus-inactivated factor VIII/von Willebrand factor concentrate (Fanhdi) in the treatment of von Willebrand disease: a retrospective clinical study. Haemophilia 2002; 8:761-767. 4. Federici, A.B. Management of von Willebrand disease with factor VIII/von Willebrand factor concentrates: results from current studies and surveys. Blood Coagul Fibrinolysis 2005; 16(Suppl 1):S17-S21. 5. Mannucci, P.M. How I treat patients with von Willebrand disease. Blood 2001; 97:1915-1919. 6. Mannucci, P.M. Treatment of von Willebrand's Disease. N Engl J Med 2004; 351:47-58. 7. Nichols, W.L. et al.; NHLBI VWD Expert Panel. The Diagnosis, Evaluation, and Management of von Willebrand Disease. US Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute 2007; NIH No. 08-5832. 8. Mannucci, P.M., Franchini, M., Castaman, G., Federici, A.B.; Italian Association of Haemophilia Centres. Evidence-based recommendations on the treatment of von Willebrand disease in Italy. Blood Transfus 2009; 7:117-126. Manufactured by: Grifols Biologicals Inc., 5555 Valley Boulevard, Los Angeles, CA 90032, U.S.A. Revised: Mar 2015

PATIENT INFORMATION XYNTHA® /ZIN-tha/ [Antihemophilic Factor (Recombinant)] for Intravenous Use, Freeze-Dried Powder Please read this patient information carefully before using XYNTHA and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical problems or your treatment. What is XYNTHA? XYNTHA is an injectable medicine that is used to help control and prevent bleeding in people with hemophilia A. Hemophilia A is also called classic hemophilia. Your healthcare provider may give you XYNTHA when you have surgery. XYNTHA is not used to treat von Willebrand's disease. What should I tell my healthcare provider before using XYNTHA? Tell your healthcare provider about all of your medical conditions, including if you: have any allergies, including allergies to hamsters. are pregnant or planning to become pregnant. It is not known if XYNTHA may harm your unborn baby. are breastfeeding. It is not known if XYNTHA passes into your milk and if it can harm your baby. Tell your healthcare provider about all of the medicines you take, including all prescription and non-prescription medicines, such as overthe- counter medicines, supplements, or herbal remedies. How should I infuse XYNTHA? Step-by-step instructions for infusing with XYNTHA are provided at the end of this leaflet. The steps listed below are general guidelines for using XYNTHA. Always follow any specific instructions from your healthcare provider. If you are unsure of the procedures, please call your healthcare provider before using. Call your healthcare provider right away if bleeding is not controlled after using XYNTHA. Your body can make antibodies against XYNTHA (called “inhibitors”) that may stop XYNTHA from working properly. Your healthcare provider may need to take blood tests from time to time to monitor for inhibitors. Call your healthcare provider right away if you take more than the dose you should take. Talk to your healthcare provider before traveling. Plan to bring enough XYNTHA for your treatment during this time. What are the possible side effects of XYNTHA? Call your healthcare provider or go to the emergency department right away if you have any of the following symptoms because these may be signs of a serious allergic reaction: wheezing difficulty breathing chest tightness turning blue (look at lips and gums) fast heartbeat swelling of the face faintness rash hives Common side effects of XYNTHA are headache fever nausea vomiting diarrhea weakness Talk to your healthcare provider about any side effect that bothers you or that does not go away. You may report side effects to FDA at 1-800-FDA-1088. How should I store XYNTHA? Store XYNTHA in the refrigerator at 36° to 46°F (2° to 8°C). Store the diluent syringe at 36° to 77°F (2° to 25°C). Do not freeze. Protect from light. XYNTHA can last at room temperature (below 77°F) for up to 3 months. If you store XYNTHA at room temperature, carefully write down the date you put XYNTHA at room temperature, so you will know when to either put it back in the refrigerator, use it immediately, or throw it away. There is a space on the carton for you to write the date. If stored at room temperature, XYNTHA can be returned one time to the refrigerator until the expiration date. Do not store at room temperature and return it to the refrigerator more than once. Throw away any unused XYNTHA after the expiration date. Infuse XYNTHA within 3 hours of reconstitution. You can keep the reconstituted solution at room temperature before infusion for up to 3 hours. If you have not used it in 3 hours, throw it away. Do not use reconstituted XYNTHA if it is not clear to slightly opalescent and colorless. Dispose of all materials, whether reconstituted or not, in an appropriate medical waste container. What else should I know about XYNTHA? Medicines are sometimes prescribed for purposes other than those listed here. Talk to your healthcare provider if you have any concerns. You can ask your healthcare provider for information about XYNTHA that was written for healthcare professionals. Do not share XYNTHA with other people, even if they have the same symptoms that you have. Instructions for Use XYNTHA /ZIN-tha/ [Antihemophilic Factor (Recombinant)] XYNTHA is supplied as a lyophilized powder. Before you can infuse it (intravenous injection), you must reconstitute the powder by mixing it with the liquid diluent supplied. The liquid diluent is 0.9% sodium chloride. Reconstitute and infuse XYNTHA using the infusion set, diluent, syringe, and adapter provided in this kit. Please follow the directions below for the proper use of this product. PREPARATION AND RECONSTITUTION OF XYNTHA Preparation Always wash your hands before doing the following steps. Keep everything clean and germ-free while you are reconstituting XYNTHA. Once the vials are open, finish reconstituting XYNTHA as soon as possible. This will help to keep them germ-free. For additional instructions on the use of a XYNTHA Vial Kit and a XYNTHA SOLOFUSE™ kit, see detailed information provided after the INFUSION OF XYNTHA section. Reconstitution Note: If you use more than one vial of XYNTHA for each infusion, reconstitute each vial according to steps 1 through 11. 1. Let the XYNTHA vial and the prefilled diluent syringe reach room temperature. 2. Remove the plastic flip-top cap from the XYNTHA vial to show the center part of the rubber stopper. 3. Wipe the top of the vial with the alcohol swab provided, or use another antiseptic solution, and allow to dry. After cleaning, do not touch the rubber stopper with your hand or allow it to touch any surface. 4. Peel back the cover from the clear plastic vial adapter package. Do not remove the adapter from the package. 5. Place the XYNTHA vial on a flat surface. While holding the adapter in the package, place the vial adapter over the XYNTHA vial. Press down firmly on the package until the adapter snaps into place on top of the vial, with the adapter spike going into the vial stopper. 6. Grasp the plunger rod as shown in the picture below. Do not touch the shaft of the plunger rod. Attach the threaded end of the plunger rod to the diluent syringe plunger by pushing and turning firmly. 7. Break off the tamper-resistant, plastic tip cap from the diluent syringe by snapping the perforation of the cap. Do not touch the inside of the cap or the syringe tip. The diluent syringe may need to be recapped (if reconstituted XYNTHA is not used immediately), so place the cap on its top on a clean surface in a spot where it will stay clean. 8. Lift the package cover away from the adapter and throw the package away. 9. Place the XYNTHA vial on a flat surface. Connect the diluent syringe to the vial adapter by inserting the tip of the syringe into the adapter opening while firmly pushing and turning the syringe clockwise until the connection is secured. 10. Slowly push the plunger rod to inject all the diluent into the XYNTHA vial. 11. With the syringe still connected to the adapter, gently swirl the contents of the vial until the powder is dissolved. Look carefully at the final solution. The solution should be clear to slightly opalescent and colorless. If it is not, throw away the solution and use a new kit. 12. Make sure the syringe plunger rod is still fully pressed down, then turn over the XYNTHA vial. Slowly pull the solution into the syringe. Turn the syringe upward again and remove any air bubbles by gently tapping the syringe with your finger and slowly pushing air out of the syringe. If you reconstituted more than one vial of XYNTHA, remove the diluent syringe from the vial adapter and leave the vial adapter attached to the XYNTHA vial. Quickly attach a separate large luer lock syringe and pull the reconstituted solution as instructed above. Repeat this procedure with each vial in turn. Do not detach the diluent syringe or the large luer lock syringe until you are ready to attach the large luer lock syringe to the next vial adapter. 13. Remove the syringe from the vial adapter by gently pulling and turning the syringe counterclockwise. Throw away the empty XYNTHA vial with the adapter attached. Note: If you are not using the solution right away, carefully replace the syringe cap. Do not touch the syringe tip or the inside of the cap. Infuse XYNTHA solution within 3 hours after reconstitution. The reconstituted solution may be kept at room temperature for up to 3 hours prior to infusion. If you have not used it in 3 hours, throw it away. INFUSION OF XYNTHA Your healthcare provider will teach you how to infuse XYNTHA yourself. Once you learn how to do this, you can follow the instructions in this insert. Before XYNTHA can be infused, you must reconstitute it as instructed above in the PREPARATION AND RECONSTITUTION OF XYNTHA section. After reconstitution, be sure to look carefully at the XYNTHA solution. The solution should be clear to slightly opalescent and colorless. If it is not, throw away the solution and use a new kit. Use the infusion set included in the kit to infuse XYNTHA. Do not infuse XYNTHA in the same tubing or container with other medicines. 1. Attach the syringe to the luer end of the provided infusion set tubing. 2. Apply a tourniquet and prepare the injection site by wiping the skin well with an alcohol swab provided in the kit. 3. Remove the protective needle cover and insert the butterfly needle of the infusion set tubing into your vein as instructed by your healthcare provider. Remove the tourniquet. Verify proper needle placement. 4. Infuse the reconstituted XYNTHA product over several minutes. Your comfort level should determine the rate of infusion. 5. After infusing XYNTHA, remove the infusion set and throw it away. The amount of liquid left in the infusion set will not affect your treatment. Note: Throw away all unused solution, the empty vial(s), and other used medical supplies in an appropriate container. It is a good idea to record the lot number from the XYNTHA vial label every time you use XYNTHA. You can use the peel-off label found on the vial to record the lot number. ADDITIONAL INSTRUCTIONS XYNTHA is also supplied in kits that have both the XYNTHA powder and the diluent within single-use prefilled dual-chamber syringes, called XYNTHA SOLOFUSE™. If you use one XYNTHA vial and one of XYNTHA SOLOFUSE™ for the infusion, reconstitute the XYNTHA vial and the XYNTHA SOLOFUSE™ according to the specific directions for that respective product kit. Use a separate 10 milliliter or larger luer lock syringe (not included in this kit) to draw back the reconstituted contents of the XYNTHA vial and XYNTHA SOLOFUSE™. Use of a XYNTHA Vial Kit with a XYNTHA SOLOFUSE™ Kit These instructions are for the use of only one XYNTHA vial kit and one XYNTHA SOLOFUSE™ Kit. For further information, please contact your healthcare provider or call the Medical Information Department at Wyeth Pharmaceuticals, 1-800-438-1985. 1. Reconstitute the XYNTHA vial using the instructions described in PREPARATION AND RECONSTITUTION OF XYNTHA section. Detach the empty diluent syringe from the vial adapter by gently turning and pulling the syringe counterclockwise, leaving the contents in the XYNTHA vial with the vial adapter in place. 2. Reconstitute the XYNTHA SOLOFUSE™ using the instructions included with the kit, remembering to remove most, but not all, of the air from the syringe. 3. After removing the protective blue vented cap, connect the XYNTHA SOLOFUSE™ to the vial adapter by inserting the tip into the adapter opening while firmly pushing and turning the syringe clockwise until secured. 4. Slowly depress the plunger rod of the XYNTHA SOLOFUSE™ until the contents empty into the XYNTHA vial. The plunger rod may move back slightly after release. 5. Detach the empty XYNTHA SOLOFUSE™ from the vial adapter and throw it away. If the syringe turns without detaching from the vial adapter, grasp the white collar and turn. 6. Connect a sterile 10 milliliter or larger luer lock syringe to the vial adapter. You may want to inject some air into the XYNTHA vial to make withdrawing the vial contents easier. 7. Invert the XYNTHA vial and slowly draw the solution into the large luer lock syringe. 8. Detach the large luer lock syringe from the vial adapter by gently turning and pulling the syringe counterclockwise. Throw away the empty XYNTHA vial with the adapter attached. 9. Attach the infusion set to the large luer lock syringe as directed in the INFUSION OF XYNTHA section. Note: Dispose of all unused solution and other used medical supplies in an appropriate container.

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections and Instructions for Use under DOSAGE AND ADMINSITRRATION.

PATIENT INFORMATION ADYNOVATE [Antihemophilic Factor (Recombinant), PEGylated] This leaflet summarizes important information about ADYNOVATE. Please read it carefully before using this medicine. This information does not take the place of talking with your healthcare provider, and it does not include all of the important information about ADYNOVATE. If you have any questions after reading this, ask your healthcare provider. What is the most important information I need to know about ADYNOVATE? Do not attempt to do an infusion to yourself unless you have been taught how by your healthcare provider or hemophilia center. You must carefully follow your healthcare provider's instructions regarding the dose and schedule for infusing ADYNOVATE so that your treatment will work best for you. What is ADYNOVATE? ADYNOVATE is an injectable medicine used to replace clotting factor (factor VIII or antihemophilic factor) that is missing in people with hemophilia A (also called “classic” hemophilia). Hemophilia A is an inherited bleeding disorder that prevents blood from clotting normally. ADYNOVATE is used on-demand to control bleeding in patients 12 years of age and older with hemophilia A. ADYNOVATE can reduce the number of bleeding episodes when used regularly (prophylaxis). ADYNOVATE is not used to treat von Willebrand disease. Who should not use ADYNOVATE? You should not use ADYNOVATE if you: Are allergic to mice or hamster protein Are allergic to any ingredients in ADYNOVATE or ADVATE Tell your healthcare provider if you are pregnant or breastfeeding because ADYNOVATE may not be right for you. How should I use ADYNOVATE? ADYNOVATE is given directly into the bloodstream. You may infuse ADYNOVATE at a hemophilia treatment center, at your healthcare provider's office or in your home. You should be trained on how to do infusions by your healthcare provider or hemophilia treatment center. Many people with hemophilia A learn to infuse their ADYNOVATE by themselves or with the help of a family member. Your healthcare provider will tell you how much ADYNOVATE to use based on your individual weight, level of physical activity, the severity of your hemophilia A, and where you are bleeding. Reconstituted product (after mixing dry product with wet diluent) must be used within 3 hours and cannot be stored or refrigerated. Discard any ADYNOVATE left in the vial at the end of your infusion as directed by your healthcare professional. You may have to have blood tests done after getting ADYNOVATE to be sure that your blood level of factor VIII is high enough to clot your blood. Call your healthcare provider right away if your bleeding does not stop after taking ADYNOVATE. What should I tell my healthcare provider before I use ADYNOVATE? You should tell your healthcare provider if you: Have or have had any medical problems. Take any medicines, including prescription and non-prescription medicines, such as overthe- counter medicines, supplements or herbal remedies. Have any allergies, including allergies to mice or hamsters. Are breastfeeding. It is not known if ADYNOVATE passes into your milk and if it can harm your baby. Are pregnant or planning to become pregnant.  It is not known if ADYNOVATE may harm your unborn baby. Have been told that you have inhibitors to factor VIII (because ADYNOVATE may not work for you). What are the possible side effects of ADYNOVATE? You can have an allergic reaction to ADYNOVATE. Call your healthcare provider right away and stop treatment if you get a rash or hives, itching, tightness of the throat, chest pain or tightness, difficulty breathing, lightheadedness, dizziness, nausea or fainting. The common side effect of ADYNOVATE is headache and nausea. Tell your healthcare provider about any side effects that bother you or do not go away. These are not all the possible side effects with ADYNOVATE. You can ask your healthcare provider for information that is written for healthcare professionals. What are the ADYNOVATE dosage strengths? ADYNOVATE comes in four different dosage strengths: 250 International Units (IU), 500 IU, 1000 IU, and 2000 IU. The actual strength will be imprinted on the label and on the box. The four different strengths are color coded, as follows: Dosage strength of approximately 250 International Units per vial (200-400 IU/vial) Dosage strength of approximately 500 International Units per vial (401-800 IU/vial) Dosage strength of approximately 1000 International Units per vial (801-1250 IU/vial) Dosage strength of approximately 2000 International Units per vial (1251-2500 IU/vial) Always check the actual dosage strength printed on the label to make sure you are using the strength prescribed by your healthcare provider. Always check the expiration date printed on the box. Do not use the product after the expiration date printed on the box. How do I store ADYNOVATE? Do not freeze. Store at refrigerated temperature 2°C to 8°C (36°F to 46°F). May store at room temperature not to exceed 30°C (86°F) for up to 1 month. Write the date on the carton when ADYNOVATE is removed from refrigeration. After storage at room temperature, do not return product back to the refrigerator. Do not use beyond the expiration date printed on the carton or vial. Store vials in their original box and protect them from extreme exposure to light. What else should I know about ADYNOVATE and Hemophilia A? Your body may form inhibitors to Factor VIII. An inhibitor is part of the body's normal defense system. If you form inhibitors, it may stop ADYNOVATE from working properly. Consult with your healthcare provider to make sure you are carefully monitored with blood tests for the development of inhibitors to Factor VIII. Medicines are sometimes prescribed for purposes other than those listed here. Do not use ADYNOVATE for a condition for which it is not prescribed. Do not share ADYNOVATE with other people, even if they have the same symptoms that you have. Instructions for Use ADYNOVATE [Antihemophilic Factor (Recombinant), PEGylated] (For intravenous use only) Do not attempt to do an infusion to yourself unless you have been taught how by your healthcare provider or hemophilia center. Step-by-step instructions for reconstituting ADYNOVATE are found at the end of this leafl et. Always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using ADYNOVATE. If you are unsure of the procedures, please call your healthcare provider before using. Call your healthcare provider right away if bleeding is not controlled after using ADYNOVATE. Your healthcare provider will prescribe the dose that you should take. Reconstituted product (after mixing dry product with wet diluent) must be used within 3 hours and cannot be stored or refrigerated. Your healthcare provider may need to take blood tests from time to time. Talk to your healthcare provider before traveling. Plan to bring enough ADYNOVATE for your treatment during this time. Dispose of all materials, including any leftover reconstituted ADYNOVATE product, in an appropriate container. 1. Prepare a clean fl at surface and gather all the materials you will need for the infusion. Check the expiration date, and let the vials with the ADYNOVATE concentrate and the Sterile Water for Injection, USP (diluent) warm up to room temperature. Wash your hands and put on clean exam gloves. If infusing yourself at home, the use of gloves is optional. If you are using more than one vial of ADYNOVATE, make sure you mix each vial of ADYNOVATE with the Sterile Water for Injection, USP that is provided in the box. Inspect the contents of the product and diluent vials. The ADYNOVATE powder should be white to off-white in color and the diluent should not contain particles. Do not use if discoloration or particles are seen. 2. Remove caps from the ADYNOVATE concentrate and diluents vials to expose the centers of the rubber stoppers. 3. Disinfect the stoppers with a sterile alcohol prep pad (or other suitable solution suggested by your healthcare provider or hemophilia center) by rubbing the stoppers firmly for several seconds and allow them to dry prior to use. Place the vials on a flat surface. 4. Open the BAXJECT II Hi-Flow device package by completely peeling away the lid, without touching the inside of the package. Do not remove the BAXJECT II Hi-flow device from the package. 5. Turn the package with the BAXJECT II Hi-Flow device upside down and place it over the top of the diluent vial. Fully insert the clear plastic spike of the device into the center of the diluent vial's stopper by pushing straight down. Grip the package at its edge and lift it off the device. Be careful not to touch the purple plastic spike. Do not remove the blue cap from the BAXJECT II Hi-Flow device. The diluent vial now has the BAXJECT II Hi-Flow device connected to it and is ready to be connected to the ADYNOVATE vial. 6. To connect the diluent vial to the ADYNOVATE vial, turn the diluent vial over and place it on top of the vial containing ADYNOVATE concentrate. Fully insert the purple plastic spike into the ADYNOVATE vial's stopper by pushing straight down. Diluent will flow into the ADYNOVATE vial. This should be done right away to keep the liquid free of germs. 7. Swirl the connected vials gently and continuously until the ADYNOVATE is completely dissolved. Do not shake. 8. Take off the blue cap from the BAXJECT II Hi-Flow device and connect the syringe. Use of a Luer-lock syringe is recommended. Be careful to not inject air. 9. Turn over the connected vials so that the ADYNOVATE vial is on top. Draw the ADYNOVATE solution into the syringe by pulling back the plunger slowly. Disconnect the syringe from the vials. Attach the infusion needle to the syringe using a winged (butterfly) infusion set, if available. Point the needle up and remove any air bubbles by gently tapping the syringe with your finger and slowly and carefully pushing air out of the syringe and needle. The ADYNOVATE solution should look clear and colorless. If not, do not use it and notify Baxalta immediately. 10. If you are using more than one vial of ADYNOVATE, the contents of more than one vial may be drawn into the same syringe (Following Steps 1-9). You will need a separate BAXJECT II Hi-Flow device to mix each additional vial of ADYNOVATE. Apply a tourniquet and get the injection site ready by wiping the skin well with a sterile alcohol prep pad (or other suitable solution suggested by your healthcare provider or hemophilia center). 11. Insert the needle into the vein and remove the tourniquet. Slowly infuse the ADYNOVATE. Do not infuse any faster than 10 mL per minute. 12. Take the needle out of the vein and use sterile gauze to put pressure on the infusion site for several minutes. 13. Do not recap the needle. Place it with the used syringe in a hard-walled Sharps container for proper disposal. 14. Remove the peel-off label from the ADYNOVATE vial and place it in your logbook. Clean any spilled blood with a freshly prepared mixture of 1 part bleach and 9 parts water, soap and water, or any household disinfecting solution. 15. Dispose of the used vials and BAXJECT II Hi-Flow device in your hard-walled sharps container without taking them apart. Do not dispose of these supplies in ordinary household trash. Important: Contact your healthcare provider or local hemophilia treatment center if you experience any problems.

PATIENT INFORMATION ELOCTATE™ /el' ok' tate / [Antihemophilic Factor (Recombinant), Fc Fusion Protein] for Intravenous Injection Please read this Patient Information carefully before using ELOCTATE and each time you get a refill, as there may be new information. This Patient Information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is ELOCTATE? ELOCTATE is an injectable medicine that is used to help control and prevent bleeding in people with Hemophilia A (congenital Factor VIII deficiency). Your healthcare provider may give you ELOCTATE when you have surgery. Who should not use ELOCTATE? You should not use ELOCTATE if you had an allergic reaction to it in the past. What should I tell my healthcare provider before using ELOCTATE? Talk to your healthcare provider about: Any medical problems that you have or had. All prescription and non-prescription medicines that you take, including over-the-counter medicines, supplements or herbal medicines. Pregnancy or if you are planning to become pregnant. It is not known if ELOCTATE may harm your unborn baby. Breastfeeding. It is not known if ELOCTATE passes into the milk and if it can harm your baby. How should I use ELOCTATE? You get ELOCTATE as an infusion into your vein. Your healthcare provider will instruct you on how to do infusions on your own, and may watch you give yourself the first dose of ELOCTATE. Contact your healthcare provider right away if bleeding is not controlled after using ELOCTATE. What are the possible side effects of ELOCTATE? Common side effects of ELOCTATE are joint pain and general discomfort. Allergic reactions may occur. Call your healthcare provider or emergency department right away if you have any of the following symptoms: difficulty breathing, chest tightness, swelling of the face, rash or hives. 20 Your body can also make antibodies called, “inhibitors,” against ELOCTATE, which may stop ELOCTATE from working properly. Your healthcare provider may give you blood tests to check for inhibitors. How should I store ELOCTATE? Keep ELOCTATE in its original package. Protect it from light. Do not freeze. Store refrigerated (2°C to 8°C or 36°F to 46°F) or at room temperature [not to exceed 30°C (86°F)], for up to six months. When storing at room temperature: Note on the carton the date on which the product is removed from refrigeration. Use the product before the end of this 6 month period or discard it. Do not return the product to the refrigerator. Do not use ELOCTATE after the expiration date printed on the vial or, if you removed it from the refrigerator, after the date that was noted on the carton, whichever is earlier. After reconstitution (mixing with the diluent): Do not use ELOCTATE if the reconstituted solution is not clear to slightly opalescent and colorless. Use reconstituted product as soon as possible You may store reconstituted solution at room temperature, not to exceed 30°C (86°F), for up to three hours. Protect the reconstituted product from direct sunlight. Discard any product not used within three hours. What else should I know about ELOCTATE? Medicines are sometimes prescribed for purposes other than those listed here. Do not use ELOCTATE for a condition for which it was not prescribed. Do not share ELOCTATE with other people, even if they have the same symptoms that you have.

PATIENT INFORMATION Novoeight® (NNO-vo-eyt) Antihemophilic Factor (Recombinant) Lyophilized Powder for Intravenous Injection Read the Patient Product Information and the Instructions For Use that come with Novoeight® before you start taking this medicine and each time you get a refill. There may be new information. This Patient Product Information does not take the place of talking with your healthcare provider about your medical condition or treatment. If you have questions about Novoeight® after reading this information, ask your healthcare provider. What is the most important information I need to know about Novoeight®? Do not attempt to do an infusion yourself unless you have been taught how by your healthcare provider or hemophilia center. You must carefully follow your healthcare provider's instructions regarding the dose and schedule for infusing Novoeight® so that your treatment will work best for you. What is Novoeight®? Novoeight® is an injectable medicine used to replace clotting factor VIII that is missing in patients with hemophilia A. Hemophilia A is an inherited bleeding disorder that prevents blood from clotting normally. Novoeight® is used to control and prevent bleeding in people with hemophilia A. Your healthcare provider may give you Novoeight® when you have surgery. Novoeight® is not used to treat von Willebrand Disease. Who should not use Novoeight®? You should not use Novoeight® if you are allergic to factor VIII or any of the other ingredients of Novoeight if you are allergic to hamster proteins Tell your healthcare provider if you are pregnant or nursing because Novoeight® might not be right for you. What should I tell my healthcare provider before I use Novoeight®? You should tell your healthcare provider if you Have or have had any medical conditions. Take any medicines, including non-prescription medicines and dietary supplements. Are nursing. Are pregnant or planning to become pregnant. Have been told that you have inhibitors to factor VIII. How should I use Novoeight®? Treatment with Novoeight® should be started by a healthcare provider who is experienced in the care of patients with hemophilia A. Novoeight® is given as an injection into the vein. You may infuse Novoeight® at a hemophilia treatment center, at your healthcare provider's office or in your home. You should be trained on how to do infusions by your hemophilia treatment center or healthcare provider. Many people with hemophilia A learn to infuse the medicine by themselves or with the help of a family member. Your healthcare provider will tell you how much Novoeight® to use based on your weight, the severity of your hemophilia A, and where you are bleeding. You may need to have blood tests done after getting Novoeight® to be sure that your blood level of factor VIII is high enough to clot your blood. This is particularly important if you are having major surgery. Your healthcare provider will calculate your dose of Novoeight® (in international units, IU) depending on your condition and body weight. Call your healthcare provider right away if your bleeding does not stop after taking Novoeight®. Development of factor VIII inhibitors Your body can also make antibodies called “inhibitors” against Novoeight®, which may stop Novoeight® from working properly. If your bleeding is not adequately controlled, it could be due to the development of factor VIII inhibitors. This should be checked by your healthcare provider. You might need a higher dose of Novoeight® or even a different product to control bleeding. Do not increase the total dose of Novoeight® to control your bleeding without consulting your healthcare provider. Use in children Novoeight® can be used in children. Your healthcare provider will decide the dose of Novoeight® you will receive. If you forget to use Novoeight® Do not inject a double dose to make up for a forgotten dose. Proceed with the next injections as scheduled and continue as advised by your healthcare provider. If you stop using Novoeight® If you stop using Novoeight® you are not protected against bleeding. Do not stop using Novoeight® without consulting your healthcare provider. If you have any further questions on the use of this product, ask your healthcare provider. What if I take too much Novoeight®? Always take Novoeight® exactly as your healthcare provider has told you. You should check with your healthcare provider if you are not sure. If you inject more Novoeight® than recommended, tell your healthcare provider as soon as possible. What are the possible side effects of Novoeight®? Common Side Effects Include: swelling or itching at the location of injection changes in liver tests fever Other Possible Side Effects: You could have an allergic reaction to coagulation factor VIII products. Call your healthcare provider right away and stop treatment if you get any of the following signs of an allergic reaction: rashes including hives difficulty breathing, shortness of breath or wheezing tightness of the chest or throat, difficulty swallowing swelling of the lips and tongue light-headedness, dizziness or loss of consciousness pale and cold skin, fast heart beat which may be signs of low blood pressure red or swollen face or hands These are not all of the possible side effects from Novoeight®. Ask your healthcare provider for more information. You are encouraged to report side effects to FDA at 1-800-FDA-1088. Tell your healthcare provider about any side effect that bothers you or that does not go away. What are the Novoeight® dosage strengths? Novoeight® comes in six different dosage strengths. The actual number of international units (IU) of factor VIII in the vial will be imprinted on the label and on the box. The six different strengths are as follows: Dosage strength of approximately 250 IU per vial Dosage strength of approximately 500 IU per vial Dosage strength of approximately 1000 IU per vial Dosage strength of approximately 1500 IU per vial Dosage strength of approximately 2000 IU per vial Dosage strength of approximately 3000 IU per vial Always check the actual dosage strength printed on the label to make sure you are using the strength prescribed by your doctor. How should I store Novoeight®? Prior to Reconstitution: Store in original package in order to protect from light. Do not freeze Novoeight®. Novoeight® vials can be stored in the refrigerator (36–46°F [2°C–8°C]) for up to 30 months or up to the expiration date, or at room temperature (up to 86°F [30°C]) for a single period not exceeding 12 months. If you choose to store Novoeight® at room temperature: Note the date that the product is removed from refrigeration on the box. The total time of storage at room temperature should not exceed 12 months. Do not return the product to the refrigerator. Do not use after 12 months from this date or the expiration date listed on the vial, whichever is earlier. Do not use this medicine after the expiration date which is on the outer carton and the vial. The expiration date refers to the last day of that month. After Reconstitution (mixing the dry powder in the vial with the diluent): The reconstituted Novoeight® should appear clear to slightly unclear without particles. The reconstituted Novoeight® should be used immediately. If you cannot use the Novoeight® immediately after it is mixed, it should be used within 4 hours when stored at ≤ 86°F (30°C). Store the reconstituted product in the vial. Keep this medicine out of the sight and out of reach of children. What else should I know about Novoeight® and hemophilia A? Medicines are sometimes prescribed for purposes other than those listed here. Do not use Novoeight® for a condition for which it is not prescribed. Do not share Novoeight® with other people, even if they have the same symptoms that you have. Instructions on how to use Novoeight® MixPro® READ THESE INSTRUCTIONS CAREFULLY BEFORE USING NOVOEIGHT®. Novoeight® is supplied as a powder. Before injection (administration) it must be mixed (reconstituted) with the liquid diluent supplied in the syringe. The liquid diluent is a sodium chloride solution. The mixed Novoeight® must be injected into your vein (intravenous injection). The equipment in this package is designed to mix and inject Novoeight®. You will also need an infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads, and bandages. Don't use the equipment without proper training from your doctor or nurse. Always wash your hands and ensure that the area around you is clean. When you prepare and inject medication directly into the veins, it is important to use a clean and germ free (aseptic) technique. Improper technique can introduce germs that can infect the blood. Don't open the equipment until you are ready to use it. Don't use the equipment if it has been dropped, or if it is damaged. Use a new package instead. Don't use the equipment if it is expired. Use a new package instead. The expiration date is printed on the outer carton and on the vial, the vial adapter and the pre-filled syringe. Don't use the equipment if you suspect it is contaminated. Use a new package instead. Don't dispose of any of the items until after you have injected the mixed solution. The equipment is for single use only. Content The package contains: Vial with Novoeight® powder Vial adapter Pre-filled syringe with diluent Plunger rod (placed under the syringe) 1. Prepare the vial and the syringe Take out the number of Novoeight®packages you need. Check the expiry date. Check the name and the color of the package, to make sure it contains the correct product. Wash your hands and dry them properly using a clean towel or air dry. Take the vial, the vial adapter and the pre-filled syringe out of the carton. Leave the plunger rod untouched in the carton. Bring the vial and the pre-filled syringe to room temperature. You can do this by holding them in your hands until they feel as warm as your hands. Figure A Remove the plastic cap from the vial. If the plastic cap is loose or missing, don't use the vial. Wipe the rubber stopper with a sterile alcohol swab and allow it to air dry for a few seconds before use to ensure that it is as germ free as possible. Don't touch the rubber stopper with your fingers as this can transfer germs. Figure B 2. Attach the vial adapter Remove the protective paper from the vial adapter. Don't take the vial adapter out of the protective cap with your fingers. If you touch the spike on the vial adapter germs from your fingers can be transferred. If the protective paper is not fully sealed or if it is broken, don't use the vial adapter. Figure C Place the vial on a flat and solid surface. Turn over the protective cap, and snap the vial adapter onto the vial. Once attached, don't remove the vial adapter from the vial. Figure D Lightly squeeze the protective cap with your thumb and index finger as shown. Remove the protective cap from the vial adapter. Don't lift the vial adapter from the vial when removing the protective cap. Figure E 3. Attach the plunger rod and the syringe Grasp the plunger rod by the wide top end and take it out of the carton. Don't touch the sides or the thread of the plunger rod. If you touch the sides or the thread germs from your fingers can be transferred. Immediately connect the plunger rod to the syringe by turning it clockwise into the rubber plunger inside the pre-filled syringe until resistance is felt. Figure F Remove the syringe cap from the pre-filled syringe by bending it down until the perforation breaks. Don't touch the syringe tip under the syringe cap. If you touch the syringe tip germs from your fingers can be transferred. If the syringe cap is loose or missing, don't use the pre-filled syringe. Figure G Screw the pre-filled syringe securely onto the vial adapter until resistance is felt. Figure H 4. Mix the powder with the diluent Hold the pre-filled syringe slightly tilted with the vial pointing downwards. Push the plunger rod to inject all the diluent into the vial. Figure I Keep the plunger rod pressed down and swirl the vial gently until all the powder is dissolved. Don't shake the vial as this will cause foaming. Check the mixed solution. It must be clear to slightly opalescent (slightly unclear). If you notice visible particles or discoloration, don't use it. Use a new package instead. Figure J Novoeight® is recommended to be used immediately after it is mixed. This is because if left, the medicine may no longer be sterile and could cause infections. If you cannot use the mixed Novoeight® solution immediately, it should be used within 4 hours when stored at ≤ 86°F (30°C). Store the reconstituted product in the vial. Do not freeze mixed Novoeight®solution or store it in syringes. Keep mixed Novoeight®solution out of direct light. If your dose requires more than one vial, repeat step A to J with additional vials, vial adapters and pre-filled syringes until you have reached your required dose. Keep the plunger rod pushed completely in. Turn the syringe with the vial upside down. Stop pushing the plunger rod and let it move back on its own while the mixed solution fills the syringe. Pull the plunger rod slightly downwards to draw the mixed solution into the syringe. In case you only need part of the entire vial, use the scale on the syringe to see how much mixed solution you withdraw, as instructed by your doctor or nurse. While holding the vial upside down, tap the syringe gently to let any air bubbles rise to the top. Push the plunger rod slowly until all air bubbles are gone. Figure K Unscrew the vial adapter with the vial. Don't touch the syringe tip. If you touch the syringe tip germs from your fingers can be transferred. Figure L Caution: The pre-filled diluent syringe is made of glass with an internal tip diameter of 0.037 inches, and is compatible with a standard Luer-lock connector. Some needleless connectors for intravenous catheters are incompatible with the glass diluent syringes (for example, certain connectors with an internal spike, such as Clave®/MicroClave®, InVision-Plus®, InVision- Plus CS®, Invision-Plus Junior®, Bionector®). The use of these needleless connectors can damage the connector and affect administration. To administer Novoeight®through incompatible needleless connectors, withdraw reconstituted product into a standard 10 mL sterile Luer-lock plastic syringe. If you have encountered any problems with attaching the pre-filled sodium chloride diluent syringe to any Luer-lock compatible device, please contact Novo Nordisk at (844) 303-4448. 5. Inject the mixed solution Novoeight® is now ready to inject into your vein. Do not mix Novoeight® with any other intravenous infusions or medications. Inject the mixed solution slowly over 2 to 5 minutes as instructed by your doctor or nurse. Injecting the solution via a central venous access device (CVAD) such as a central venous catheter or subcutaneous port: Use a clean and germ free (aseptic) technique. Follow the instructions for proper use for your connector and central venous access device in consultation with your doctor or nurse. Injecting into a CVAD may require using a sterile 10 mL plastic syringe for withdrawal of the mixed solution and injection. If necessary, use 0.9% Sodium Chloride Injection, USP to flush the CVAD line before or after Novoeight® injection. The peel-off label found on the Novoeight® vial can be used to record the lot number. Disposal After injection, safely dispose of all unused Novoeight® solution, the syringe with the infusion set, the vial with the vial adapter, and other waste materials in an appropriate container for throwing away medical waste. Don't throw it out with the ordinary household trash. Figure M Don't disassemble the vial and vial adapter before disposal. Don't reuse the equipment. Important information Contact your healthcare provider or local hemophilia treatment center if you experience any problems. For full Prescribing Information please read the other insert included in this package.

PATIENT INFORMATION KOVALTRY (KOH-vahl-tree) Antihemophilic Factor (Recombinant) This leaflet summarizes important information about KOVALTRY with vial adapter. Please read it carefully before using this medicine. This information does not take the place of talking with your healthcare provider, and it does not include all of the important information about KOVALTRY. If you have any questions after reading this, ask your healthcare provider. Do not attempt to self-infuse unless you have been taught how by your healthcare provider or hemophilia center. What is KOVALTRY? KOVALTRY is a medicine used to replace clotting factor (Factor VIII or antihemophilic factor) that is missing in people with hemophilia A (also called “classic” hemophilia). Hemophilia A is an inherited bleeding disorder that prevents blood from clotting normally. KOVALTRY is used to treat and control bleeding in adults and children with hemophilia A. Your healthcare provider may give you KOVALTRY when you have surgery. KOVALTRY can reduce the number of bleeding episodes in adults and children with hemophilia A when used regularly (prophylaxis). KOVALTRY is not used to treat von Willebrand Disease. Who should not use KOVALTRY? You should not use KOVALTRY if you are allergic to rodents (like mice and hamsters). are allergic to any ingredients in KOVALTRY. What should I tell my healthcare provider before I use KOVALTRY? Tell your healthcare provider about all of your medical conditions. Tell your healthcare provider and pharmacist about all of the medicines you take, including all prescription and non-prescription medicines, such as over-the-counter medicines, supplements, or herbal remedies. Tell your healthcare provider if you have been told you have heart disease or are at risk for heart disease. Tell your healthcare provider if you have been told that you have inhibitors to Factor VIII (because KOVALTRY may not work for you). What are the possible side effects of KOVALTRY? The common side effects of KOVALTRY are headache, fever and itchy rash. Allergic reactions may occur with KOVALTRY. Call your healthcare provider right away and stop treatment if you get tightness of the chest or throat, dizziness, decrease in blood pressure, and nausea. Your body can also make antibodies, called “inhibitors,” against KOVALTRY, which may stop KOVALTRY from working properly. Consult with your healthcare provider to make sure you are carefully monitored with blood tests for the development of inhibitors to Factor VIII. These are not all the possible side effects with KOVALTRY. You can ask your healthcare provider for information that is written for healthcare professionals. Tell your healthcare provider about any side effect that bothers you or that does not go away. What are the KOVALTRY dosage strengths? KOVALTRY with 2.5 mL or 5 mL Sterile Water for Injection (SWFI) comes in five different dosage strengths labeled as International Units (IU): 250 IU, 500 IU, 1000 IU, 2000 IU, and 3000 IU. The five different strengths are color-coded as follows: Blue 250 IU with 2.5 mL SWFI Green 500 IU with 2.5 mL SWFI Red 1000 IU with 2.5 mL SWFI Yellow 2000 IU with 5 mL SWFI Gray 3000 IU with 5 mL SWFI How do I store KOVALTRY? Do not freeze KOVALTRY. Store KOVALTRY at +2°C to +8°C (36°F to 46°F) for up to 30 months from the date of manufacture. Within this period, KOVALTRY may be stored for a period of up to 12 months at temperatures up to +25°C or 77°F. Record the starting date of room temperature storage clearly on the unopened product carton. Once stored at room temperature, do not return the product to the refrigerator. The product then expires after storage at room temperature for 12 months, or after the expiration date on the product vial, whichever is earlier. Store vials in their original carton and protect them from extreme exposure to light. Administer reconstituted KOVALTRY as soon as possible. If not, store at room temperature for no longer than 3 hours. Throw away any unused KOVALTRY after the expiration date. Do not use reconstituted KOVALTRY if it is not clear. What else should I know about KOVALTRY and hemophilia A? Finding veins for injections may be difficult in young children. When frequent injections are required, your healthcare provider may propose to have a device surgically placed under the skin to facilitate access to the bloodstream. These devices may result in infections. Medicines are sometimes prescribed for purposes other than those listed here. Do not use KOVALTRY for a condition for which it is not prescribed. Do not share KOVALTRY with other people, even if they have the same symptoms that you have. This leaflet summarizes the most important information about KOVALTRY. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about KOVALTRY that was written for healthcare professionals. Instructions for Use KOVALTRY (KOH-vahl-tree) Antihemophilic Factor (Recombinant) Do not attempt to self-infuse unless you have been taught how by your healthcare provider or hemophilia center. You should always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using KOVALTRY. If you are unsure of the procedures, please call your healthcare provider before using. Call your healthcare provider right away if bleeding is not controlled after using KOVALTRY. Your healthcare provider will prescribe the dose that you should take. Your healthcare provider may need to take blood tests from time to time. Talk to your healthcare provider before traveling. You should plan to bring enough KOVALTRY for your treatment during this time. See the step-by-step instructions below for reconstituting KOVALTRY with vial adapter. Follow the specific infusion instruction leaflet included with the infusion set provided. Carefully handle KOVALTRY. Dispose of all materials, including any leftover reconstituted KOVALTRY product, in an appropriate container. Reconstitution Always work on a clean surface and wash your hands before performing the following procedure. Use only the components for reconstitution and administration that are provided with each package of KOVALTRY. If a package is opened or damaged, do not use this component. If these components cannot be used, please contact your healthcare provider. Prepare a clean flat surface and gather all the materials needed for the infusion. 1. Warm the unopened diluent syringe and the concentrate vial to a temperature not to exceed 37°C or 99°F. 2. Remove protective cap from the vial (A). Aseptically cleanse the rubber stopper with a sterile alcohol swab, being careful not to handle the rubber stopper. Figure A 3. Place product vial on a firm, non-skid surface. Peel off the paper cover on the vial adapter plastic housing. Do not remove the adapter from the plastic housing. Holding the adapter housing, place over the product vial and firmly press down (B). The adapter will snap over the vial cap. Do not remove the adapter housing at this step. Figure B 4. Holding the syringe by the barrel, snap the syringe cap off the tip (C). Do not touch the syringe tip with your hand or any surface. Set the syringe aside for further use. Figure C 5. Now remove and discard the adapter plastic housing (D). Figure D 6. Attach the prefilled syringe to the vial adapter thread by turning clockwise (E). Figure E 7. Remove the clear plastic plunger rod from the carton. Grasp the plunger rod by the top plate. Avoid touching the sides and threads of the plunger rod. Attach the plunger rod by turning it clockwise into the threaded rubber stopper of the prefilled syringe (F). Figure F 8. Inject the diluent slowly by pushing down on the plunger rod (G). Figure G 9. Swirl vial gently until all powder on all sides of the vial is dissolved (H). Do not shake vial. Be sure that all powder is completely dissolved. Do not use if solution contains visible particles or is cloudy. Figure H 10. Push down on the plunger to push all air back into the vial. Then while holding the plunger down, turn the vial with syringe upside-down (invert) so the vial is now above the syringe (I). Figure I 11. Withdraw all the solution into the syringe by pulling the plunger rod back slowly and smoothly (J). Tilt the vial to the side and back to make sure all the solution has been drawn toward the large opening in the rubber stopper and into the syringe. Remove as much air as possible before removing the syringe from the vial by slowly and carefully pushing the air back into the vial. Figure J 12. Detach the syringe with plunger rod from the vial adapter by turning counter-clockwise. Attach the syringe to the administration set provided and inject intravenously (K). NOTE: follow instructions for infusion set provided. Figure K Pooling If the dose requires more than one vial, reconstitute each vial as described above with the diluent syringe provided. To combine the content of the vials, use a larger plastic syringe (not provided) to pool the solution into the syringe and administer as usual. Rate of Administration The entire dose of KOVALTRY can usually be infused within 1 to 15 minutes. Your healthcare provider will determine the rate of administration that is best for you. Resources at Bayer available to the patient: For Adverse Reaction Reporting, contact Bayer Medical Communications 1-888-84-BAYER (1-888-842-2937) To receive more product information, contact KOVALTRY Customer Service 1-888-606-3780 Bayer Reimbursement HELPline 1-800-288-8374 For more information, visit www.KOVALTRY-us.com

PATIENT INFORMATION The patient and physician should discuss the risks and benefits of this product. Although allergic type hypersensitivity reactions were not observed in any patient receiving RECOMBINATE (antihemophilic factor (recombinant)) rAHF on study, such reactions are theoretically possible. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physician if these symptoms occur.

PATIENT INFORMATION Kogenate FS (ko-jen-ate) Antihemophilic Factor (Recombinant) Formulated with Sucrose This leaflet summarizes important information about Kogenate FS. Please read it carefully before using this medicine. This information does not take the place of talking with your healthcare provider, and it does not include all of the important information about Kogenate FS. If you have any questions after reading this, ask your healthcare provider. Do not attempt to self-infuse unless you have been taught how by your healthcare provider or hemophilia center. What is Kogenate FS? Kogenate FS is a medicine used to replace clotting factor (factor VIII or antihemophilic factor) that is missing in people with hemophilia A (also called “classic” hemophilia). Hemophilia A is an inherited bleeding disorder that prevents blood from clotting normally. Kogenate FS is used to prevent and control bleeding in adults and children (0-16 years) with hemophilia A. Your healthcare provider may give you Kogenate FS when you have surgery. Kogenate FS can reduce the number of bleeding episodes when used regularly and reduce the risk of joint damage in children. Kogenate FS is not used to treat von Willebrand's Disease. Who should not use Kogenate FS? You should not use Kogenate FS if you are allergic to rodents (like mice and hamsters). are allergic to any ingredients in Kogenate FS. Tell your healthcare provider if you are pregnant or breast-feeding because Kogenate FS may not be right for you. What should I tell my healthcare provider before I use Kogenate FS? Tell your healthcare provider about all of your medical conditions. Tell your healthcare provider and pharmacist about all of the medicines you take, including all prescription and nonprescription medicines, such as over-the-counter medicines, supplements, or herbal remedies. Tell your healthcare provider if you have been told that you have inhibitors to factor VIII (because Kogenate FS may not work for you). What are the possible side effects of Kogenate FS? You could have an allergic reaction to Kogenate FS. Call your healthcare provider right away and stop treatment if you get rash or hives itching tightness of the chest or throat difficulty breathing light-headed, dizziness nausea decrease in blood pressure Your body can also make antibodies, called “inhibitors,” against Kogenate FS, which may stop Kogenate FS from working properly. Consult with your healthcare provider to make sure you are carefully monitored with blood tests for the development of inhibitors to factor VIII. Other common side effects of Kogenate FS are Local injection site reactions (pain, swelling, irritation at infusion site) Infections from implanted injection device Tell your healthcare provider about any side effect that bothers you or that does not go away. Finding veins for injections may be difficult in young children. When frequent injections are required your child's healthcare provider may propose to have a device surgically placed under the skin to facilitate access to the bloodstream. These devices may result in infections. These are not all the possible side effects with Kogenate FS. You can ask your healthcare provider for information that is written for healthcare professionals. How do I store Kogenate FS? Do not freeze Kogenate FS. Store Kogenate FS at +2°C to +8°C (36°F to 46°F) for up to 30 months from the date of manufacture. Within this period, Kogenate FS may be stored for a period of up to 12 months at temperatures up to +25°C or 77°F. The starting date of room temperature storage should be clearly recorded on the unopened product carton. Once stored at room temperature, the product must not be returned to the refrigerator. The shelf-life then expires after the storage at room temperature, or the expiration date on the product vial, whichever is earlier. Store vials in their original carton and protect them from extreme exposure to light. Reconstituted product (after mixing dry products with wet diluent) must be used within 3 hours and cannot be stored. Throw away any unused Kogenate FS after the expiration date. Do not use reconstituted Kogenate FS if it is not clear to slightly cloudy and colorless. What else should I know about Kogenate FS and hemophilia A? Medicines are sometimes prescribed for purposes other than those listed here. Do not use Kogenate FS for a condition for which it is not prescribed. Do not share Kogenate FS with other people, even if they have the same symptoms that you have. This leaflet summarizes the most important information about Kogenate FS. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about Kogenate FS that was written for healthcare professionals. Instructions for use How should I take Kogenate FS? Do not attempt to self-infuse unless you have been taught how by your healthcare provider or hemophilia center. See the step-by-step instructions for reconstituting Kogenate FS at the end of this leaflet and the specific infusion instruction leaflet provided. You should always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using Kogenate FS. If you are unsure of the procedures, please call your healthcare provider before using. Call your healthcare provider right away if bleeding is not controlled after using Kogenate FS. Your healthcare provider will prescribe the dose that you should take. Your healthcare provider may need to take blood tests from time to time. Talk to your healthcare provider before traveling. You should plan to bring enough Kogenate FS for your treatment during this time. Carefully handle Kogenate FS. Dispose of all materials, including any leftover reconstituted Kogenate FS product, in an appropriate container. Reconstitution and use of Kogenate FS Always work on a clean surface and wash your hands before performing the following procedure. Use only the components for reconstitution and administration that are provided with each package of Kogenate FS. If a package is opened or damaged, do not use this component. If these components cannot be used, please contact your healthcare provider. If you have any questions about Kogenate FS contact Bayer at 1-888-84-BAYER (1-888-842-2937). 1. Warm the unopened diluent and the concentrate to a temperature not to exceed 37°C or 99°F. 2. After removing the plastic flip-top caps (Fig. A), clean the rubber stoppers of both bottles with alcohol wipes. Be careful not to handle the rubber stopper. Figure A 3. Remove the cover from one end of the plastic transfer needle cartridge and insert into the stopper of the diluent bottle (Fig. B). Figure B 4. Remove the rest of the cover from the needle cartridge. Turn over the diluent bottle. With the needle at an angle, insert into the rubber seal on the concentrate bottle (Fig. C). Figure C 5. The vacuum will suck the diluent into the concentrate bottle. Hold the diluent bottle at an angle to the concentrate bottle in order to direct the stream of diluent against the wall of the concentrate bottle (Fig. C). Avoid too much foaming. If the diluent does not get into the bottle, the product should not be used. 6. Remove the diluent bottle and transfer needle (Fig. D). Gently, swirl the bottle until the Kogenate FS infusion liquid is dissolved. Be careful not to create foam (Fig. E). Throw away any liquid that is cloudy, the wrong color, or contains particles. Figure D and E 7. Clean the stopper of the Kogenate FS infusion liquid bottle with an alcohol wipe. Allow the stopper to air dry. 8. Using the filter needle from the infusion set, suck the infusion liquid into the syringe (Fig. F). Replace the filter needle with the vein needle from the infusion set and follow the specific instructions for infusion provided in the accompanying infusion set leaflet. Figure F 9. If the same patient is getting more than one bottle for an infusion, the contents of two infusion liquid bottles can be sucked into the same syringe using separate unused filter needles before attaching the vein needle. Rate of administration The entire dose of Kogenate FS can usually be infused within 1 to 15 minutes. However, your healthcare provider will determine the rate of administration that is best for you. Resources at Bayer available to the patient: For Adverse Reaction Reporting contact: Bayer Medical Communications 1-888-84-BAYER (1-888-842-2937). Contact Bayer to receive more product information: Kogenate FS Customer Service 1-888-606-3780. Bayer Reimbursement HELPline 1-800-288-8374. For more information, visit www.kogenatefs.com

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

PATIENT INFORMATION Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis, and should be advised to discontinue use of the concentrate and contact their physician if these symptoms occur. Some viruses, such as parvovirus B19 or hepatitis A, are particularly difficult to remove or inactivate at this time. Parvovirus B19 most seriously affects pregnant women, or immunecompromised individuals. Although the overwhelming number of hepatitis A and parvovirus B19 cases are community acquired, there have been reports of these infections associated with the use of some plasma-derived products. Therefore, physicians should be alert to the potential symptoms of parvovirus B19 and hepatitis A infections and inform patients under their supervision receiving plasma derived products to report potential symptoms promptly. Symptoms of parvovirus B19 include fever, drowsiness, chills and runny nose followed two weeks later by a rash and joint pain. Evidence of hepatitis A may include several days to weeks of poor appetite, tiredness, and low-grade fever followed by nausea, vomiting and pain in the belly. Dark urine and a yellowed complexion are also common symptoms. Patients should be encouraged to consult their physicians if such symptoms occur.

PATIENT INFORMATION Some viruses, such as parvovirus B19 or hepatitis A, are particularly difficult to remove or inactivate at this time. Parvovirus B19 most seriously affects pregnant women, or immune-compromised individuals. Symptoms of parvovirus B19 infection include fever, drowsiness, chills and runny nose followed about 2 weeks later by a rash and joint pain. Evidence of hepatitis A may include several days to weeks of poor appetite, tiredness, and low-grade fever followed by nausea, vomiting, and pain in the belly. Dark urine and a yellowed complexion are also common symptoms. Patients should be encouraged to consult their physician if such symptoms appear.

PATIENT INFORMATION Although allergic type hypersensitivity reactions were not observed in any patient receiving Bioclate (antihemophilic factor) † on study, such reactions are theoretically possible. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physician if these symptoms occur.

OVERDOSE No information provided. CONTRAINDICATIONS XYNTHA is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster proteins.

OVERDOSE No information provided. CONTRAINDICATIONS Known hypersensitivity to mouse or hamster proteins may be a contraindication to the use of ReFacto® Antihemophilic Factor (Recombinant).

OVERDOSE No information provided. CONTRAINDICATIONS OBIZUR is contraindicated in patients who have had life-threatening hypersensitivity reactions to OBIZUR or its components (including traces of hamster proteins).

OVERDOSE No information provided. CONTRAINDICATIONS ADYNOVATE is contraindicated in patients who have had prior anaphylactic reaction to ADYNOVATE, to the parent molecule (ADVATE), mouse or hamster protein, or excipients of ADYNOVATE (e.g. Tris, mannitol, trehalose, glutathione, and/or polysorbate 80).

OVERDOSE No information provided. CONTRAINDICATIONS ELOCTATE is contraindicated in patients who have had life-threatening hypersensitivity reactions to ELOCTATE, including anaphylaxis.

OVERDOSE No information provided. CONTRAINDICATIONS Novoeight® is contraindicated in patients who have had life-threatening hypersensitivity reactions, including anaphylaxis, to Novoeight® or its components (including traces of hamster proteins).

OVERDOSE No information provided. CONTRAINDICATIONS KOVALTRY is contraindicated in patients who have a history of hypersensitivity reactions to the active substance, to any of the excipients, or to mouse or hamster proteins [see DESCRIPTION].

OVERDOSE No information provided. CONTRAINDICATIONS Known hypersensitivity to mouse, hamster or bovine protein may be a contraindication to the use of Antihemophilic Factor (Recombinant) (see PRECAUTIONS).

OVERDOSE No information provided. CONTRAINDICATIONS Kogenate FS is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including mouse or hamster proteins.

OVERDOSE No information provided. CONTRAINDICATIONS Known intolerance or allergic reactions to constituents of the preparation. Known hypersensitivity to mouse or hamster protein may be a contraindication to the use of Helixate FS (antihemophilic factor (recombinant)) .

OVERDOSE No information provided. CONTRAINDICATIONS Known hypersensitivity to mouse protein is a contraindication to Monoclate-P®.

OVERDOSE No information provided. CONTRAINDICATIONS None known.

OVERDOSE No infrormation provided. CONTRAINDICATIONS Known hypersensitivity to mouse, hamster or bovine protein may be a contraindication to the use of Antihemophilic Factor (Recombinant) (see PRECAUTIONS).

OVERDOSE No information provided. CONTRAINDICATIONS ALPHANATE is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components [see ADVERSE REACTIONS].

SIDE EFFECTS The most common adverse reactions ( ≥ 10%) with XYNTHA in adult and pediatric PTPs were headache, arthralgia, pyrexia, and cough. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. XYNTHA was evaluated in five clinical studies (N=155), four completed studies with adult and pediatric PTPs and one ongoing study in pediatric PTPs < 6 years of age. The safety and efficacy of XYNTHA was evaluated in two completed pivotal studies. In the first study (n=94), safety and efficacy were examined in previously treated patients (PTPs) with hemophilia A (factor VIII activity in plasma [FVIII:C] ≤ 2%)who received XYNTHA for routine prophylaxis and on-demand treatment. Ninety-four subjects received at least one dose of XYNTHA, resulting in a total of 6,775 infusions [see Clinical Studies]. The second study (n=30) examined the use of XYNTHA for surgical prophylaxis in previously treated patients with severe or moderately severe hemophilia A (FVIII:C ≤ 2%) who required elective major surgery and were expected to receive XYNTHA replacement therapy for at least 6 days post-surgery. All subjects received at least one dose of XYNTHA, resulting in 1161 infusions. One subject received XYNTHA for a pre-surgery pharmacokinetic assessment only and did not undergo surgery. [see Clinical Studies] Across all studies, safety was evaluated in 48 previously treated pediatric patients < 16 years of age (28 children, < 6 years of age and 20 adolescents, 12 to < 16 years of age). A total of 7,150 infusions of XYNTHA were administered with a median dose per infusion of 29 IU/kg (min, max: 9,108 IU/kg). Across all studies, the most common adverse reactions ( ≥ 10%) with XYNTHA in adult and pediatric PTPs were headache (26% of subjects), arthralgia (25%), pyrexia (21%), cough (11%). Other adverse reactions reported in ≥ 5% of subjects were: diarrhea (8%), vomiting (7%), asthenia (7%), and nausea (6%). Immunogenicity There is a potential for immunogenicity with therapeutic proteins. The development of factor VIII inhibitors with XYNTHA was evaluated in 144 adult and pediatric PTPs with at least 50 EDs. Laboratory-based assessments for FVIII inhibitor (partial Nijmegen modification of the Bethesda inhibitor assay) were conducted in the clinical studies. The criterion for a positive FVIII result test result was ≥ 0.6 BU/mL. Across all studies, 3 subjects developed factor VIII inhibitors (2.1%). The clinical studies for XYNTHA examined 124 subjects (94 for bleeding and 30 for surgery) who had previously been treated with factor VIII (PTPs). In the safety and efficacy study, two subjects with inhibitors were observed in 89 subjects (2.2%) who completed ≥ 50 exposure days. In a Bayesian statistical analysis, results from this study were used to update PTP results from a prior supporting study using XYNTHA manufactured at the initial facility (with one de novo and two recurrent inhibitors observed in 110 subjects) and the experience with predecessor product (with one inhibitor observed in 113 subjects). The Bayesian analysis indicated that the population inhibitor rate for XYNTHA, an estimate of the 95% upper limit of the true inhibitor rate, was 4.17%. None of the PTPs developed anti-CHO (Chinese hamster ovary) or anti-TN8.2 antibodies. One PTP developed anti-FVIII antibodies; but, this subject did not develop an inhibitor. In the surgery study, one low titer persistent inhibitor and one transient false-positive inhibitor were reported. In this study, one surgical subject developed anti-CHO cell antibodies with no associated allergic reaction. One subject developed anti-FVIII antibodies; but, this subject did not develop an inhibitor. Across all studies, safety was evaluated in 40 previously treated pediatric patients < 16 years of age with at least 50 EDs (25 children, < 6 years of age and 15 adolescents, 12 to < 16 years of age). Of these, one pediatric subject developed an inhibitor. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody, including neutralizing antibody, positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparisons of the incidence of antibodies to XYNTHA with the incidence of antibodies to other products may be misleading. Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following postmarketing adverse reactions have been reported for XYNTHA: Anaphylaxis Inadequate therapeutic response DRUG INTERACTIONS No information provided.

SIDE EFFECTS In phase 3 clinical studies of ReFacto (antihemophilic factor) involving a total of 218 study subjects (113 PTPs, 101 PUPs, and 4 PTPs who participated in the surgery study only), more than 138 million IU were administered during a total of 75,757 exposure days. The 113 PTPs in the long-term PTP study were given a median of 327 injections (range 4-1769 injections) over a median of 313 exposure days (range 4-1312 days). The 101 PUPs in the long-term PUP study were given a median of 218 injections (range 1-1476 injections) over a median of 197 exposure days (range 1-1466 days). As with the intravenous administration of any protein product, the following reactions may be observed after administration: headache, fever, chills, flushing, nausea, vomiting, lethargy, or manifestations of allergic reactions. During phase 3 clinical studies with ReFacto® Antihemophilic Factor (Recombinant), 278 adverse reactions were probably or possibly related or of unknown relation to therapy with 80,370 infusions (0.35% of infusions) in 109 of 218 study subjects (50%). Adverse reactions reported by ≥ 1% of study subjects are presented in Tables 2 and 3 for PTPs and PUPs, respectively. One of 218 subjects experienced hypotension that was mild in severity and considered probably related to the administration of ReFacto (antihemophilic factor) as noted in Table 3. TABLE 2. SUMMARY OF STUDY-DRUG RELATED ADVERSE EVENTS IN ≥ 1% OF PTPS Body system No. of Events No. of Subjects Eventa n=145 n=113 n (%) n (%) Body as a whole Asthenia 2 (1.4) 2 (1.8) Chills 2 (1.4) 2 (1.8) Headache 5 (3.4) 4 (3.5) Injection site pain 5 (3.4) 2 (1.8) Cardiovascular system Hemorrhage 2 (1.4) 2 (1.8) Digestive system Nausea 25 (17.2) 5 (4.4) Hemic and lymphatic system FVIII AB lab increase (ELISA) 4 (2.8) 4 (3.5) CHO AB lab increase (ELISA) 19 (13.1) 16 (14.2) Mouse IgG AB lab increase (ELISA) 4 (2.8) 4 (3.5) Nervous system Dizziness 4 (2.8) 4 (3.5) Respiratory system Dyspnea 6 (4.1) 2 (1.8) Skin and appendages Pruritus 34 (23.4) 2 (1.8) Special senses Taste perversion 3 (2.1) 3 (2.7) a: Includes events for 113 PTPs during their participation in the long-term study and surgery study. The 4 PTPs who participated in the surgery study only had no adverse events that were study-drug related. TABLE 3. SUMMARY OF STUDY-DRUG RELATED ADVERSE EVENTS IN ≥ 1% OF PUPS Body system No. of Events No. of Subjects Eventa n=133 n=101 n (%) n (%) Body as a whole Abdominal pain 1 (0.8) 1 (1.0) Anaphylactoid reaction 1 (0.8) 1 (1.0) Asthenia 1 (0.8) 1 (1.0) Catheter infection 1 (0.8) 1 (1.0) Catheter misc 1 (0.8) 1 (1.0) Catheter thrombosis 2 (1.5) 2 (2.0) Edema 1 (0.8) 1 (1.0) Fever 6 (4.5) 6 (5.9) Infection 1 (0.8) 1 (1.0) Injection site reaction 1 (0.8) 1 (1.0) Pain 2 (1.5) 2 (2.0) Cardiovascular system Hemorrhage 1 (0.8) 1 (1.0) Hypotension 1 (0.8) 1 (1.0) Vasodilatation 1 (0.8) 1 (1.0) Digestive system Anorexia 1 (0.8) 1 (1.0) Diarrhea 1 (0.8) 1 (1.0) Gastrointestinal hemorrhage 1 (0.8) 1 (1.0) Nausea 1 (0.8) 1 (1.0) Hemic and lymphatic system FVIII inhibitor 32 (24.1) 32 (31.7) FVIII AB lab increase (ELISA) 31 (23.3) 26 (25.7) CHO AB lab increase (ELISA) 20 (15.0) 17 (16.8) Mouse IgG AB lab increase (ELISA) 17 (12.8) 12 (11.9) Metabolic and nutritional disorders SGOT increased 1 (0.8) 1 (1.0) Musculoskeletal system Arthralgia 1 (0.8) 1 (1.0) Nervous system Somnolence 1 (0.8) 1 (1.0) Respiratory system Rhinitis 1 (0.8) 1 (1.0) Skin and appendages Rash 1 (0.8) 1 (1.0) Urticaria 1 (0.8) 1 (1.0) Urogenital system Urinary tract infection 2 (1.5) 1 (1.0) a: Includes events for 101 PUPs during their participation in the long-term study and surgery study. If any adverse reaction takes place that is thought to be related to administration of ReFacto (antihemophilic factor) , the rate of infusion should be decreased or stopped. Inhibitor development is a known adverse event associated with the treatment of patients with hemophilia A. In addition to the one report of a high-titer inhibitor in the clinical study of PTPs (see CLINICAL PHARMACOLOGY), there have been reports of high-titer inhibitors in PTPs in the post-marketing setting. High- and low-titer inhibitors have been reported in PUPs in both clinical trials and the post-marketing setting (see PRECAUTIONS, General). Other adverse experiences that were reported during the clinical trials, but which were assessed by both the investigator and the sponsor as “unlikely” to be related to ReFacto (antihemophilic factor) administration included: dyspnea (3), rash (2), pruritus (1), neuropathy (1), arm weakness (1), and thrombophlebitis of upper arm (1). DRUG INTERACTIONS No information provided.

SIDE EFFECTS Common adverse reactions observed in greater than 5% of subjects in the clinical trial were development of inhibitors to porcine factor VIII. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction (AR) rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety and efficacy of OBIZUR was evaluated in a multi-center, prospective, open-label, clinical trial that investigated adult patients with acquired hemophilia A. Twenty-nine adult subjects were enrolled in the study, received at least one dose of OBIZUR and were evaluable for safety [see Clinical Studies]. Of the 29 adult subjects, 10 were between the ages of 40 and 65, and 19 were 65 years of age or older (18 Caucasian, 6 African-American, and 5 Asian). Ten (34%) subjects were female. The most frequently reported adverse reaction in patients with acquired hemophilia A was the development of inhibitors to porcine factor VIII. Immunogenicity All subjects were monitored for development of inhibitory antibodies to OBIZUR using the Nijmegen modification of the Bethesda inhibitor assay. A subject was considered to have developed an OBIZUR inhibitor if the titer was ≥ 0.6 Bethesda Units (BU)/mL. Of the 29 subjects treated with OBIZUR, 19 subjects were negative for anti-porcine factor VIII antibodies at baseline. Five of the 19 (26%) developed anti-porcine factor VIII antibodies following exposure to OBIZUR. Of the 10 subjects with detectable anti-porcine factor VIII antibodies at baseline, 2 (20%) experienced an increase in titer and eight (80%) experienced a decreasing to a non-detectable titer. All subjects were also monitored for development of binding antibodies to baby hamster kidney (BHK) protein by a validated sequential ELISA (enzyme-linked immunosorbent assay). No patients developed de novo anti-BHK antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to OBIZUR with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS No information provided.

SIDE EFFECTS Common adverse reactions ( ≥ 1% of subjects) reported in the clinical studies were headache and nausea. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not refl ect the rates observed in practice. The safety of ADYNOVATE was evaluated in 169 previously treated patients (PTPs) with severe hemophilia A (factor VIII less than 1% of normal), who received at least one dose of ADYNOVATE in 2 multi-center, prospective, open label clinical studies and 3 ongoing clinical studies. The median duration of participation per subject was 333 (min-max: 1-593) days and the median number of exposure days to ADYNOVATE per subject was 96 (min-max: 1-170). Table 2 lists the adverse reactions reported during clinical studies. Table 2: Adverse Reactions Reported for ADYNOVATE MedDRA System Organ Class MedDRA Preferred Term Number of Subjects n (%) (N=169) Percent of Infusion (N=13579) Gastrointestinal Disorders Diarrhea 1 (0.6%) 0.01% Nausea 2 (1.2%) 0.01% Nervous System Disorders Headache 5 (3.0%) 0.06% Vascular Disorders Flushing 1 (0.6%) 0.01% No events of hypersensitivity were reported. Two cases of acute pancreatitis, with no precipitating cause identified in one case, were reported in adults during an extension study of the clinical trial which evaluated 137 subjects. Administration of ADYNOVATE continued and both cases resolved. Immunogenicity The risk of the development of factor VIII inhibitors with the use of ADYNOVATE was evaluated in 2 completed and 3 ongoing clinical trials. Study subjects consisted of adult (n= 143 with ≥ prior 150 EDs) and pediatric PTPs [( < 6 years of age with ≥ 50 prior EDs (n= 3), ≥ 6 years of age with ≥ 150 prior EDs (n= 23)]. In 120 adult and pediatric PTPs who were treated for at least 50 exposure days with ADYNOVATE, the factor VIII inhibitor frequency was 0 (95% CI of 0 to 0.03). None of the 169 individual subjects who received at least one infusion of ADYNOVATE developed neutralizing antibodies to factor VIII. Immunogenicity also was evaluated by measuring the development of binding IgG and IgM antibodies against factor VIII, PEGylated (PEG)-factor VIII, PEG and Chinese hamster ovary (CHO) protein using validated ELISA assays. None of the 169 treated subjects with at least one infusion of ADYNOVATE developed a persistent binding antibody response to any of these antigens. Thirteen subjects in total showed pre-existing antibodies to factor VIII (n=1), PEG-factor VIII (n=12) and/or PEG (n=3) prior to the first exposure to ADYNOVATE. Eight subjects who tested negative at screening developed transient IgG antibodies against factor VIII (n= 5), or PEG-FVIII (n= 3) at one or two consecutive study visits. Binding antibodies that were detected prior to exposure to ADYNOVATE or that transiently developed during the study could not be correlated to any impaired treatment efficacy, altered PK parameters, or adverse reactions. No subject had pre-existing or treatment-emergent antibodies to CHO protein. The detection of antibodies that are reactive to factor VIII is highly dependent on many factors, including: the sensitivity and specificity of the assay, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ADYNOVATE with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS No information provided.

SIDE EFFECTS Common adverse reactions ( ≥ 1% of subjects) reported in clinical trials were arthralgia and malaise. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. In the multi-center, prospective, open-label, clinical trial of ELOCTATE, 164 adolescent and adult, previously treated patients (PTPs, exposed to a Factor VIII containing product for ≥ 150 exposure days) with severe Hemophilia A ( < 1% endogenous FVIII activity or a genetic mutation consistent with severe Hemophilia A) received at least one dose of ELOCTATE as part of either routine prophylaxis, on-demand treatment of bleeding episodes or perioperative management. A total of 146 (89%) subjects were treated for at least 26 weeks and 23 (14%) subjects were treated for at least 39 weeks. Adverse reactions (ARs) (summarized in Table 3) were reported for nine (5.5 %) subjects treated with routine prophylaxis or episodic (on-demand) therapy. Two subjects were withdrawn from study due to adverse reactions of rash and arthralgia. In the study, no inhibitors were detected and no events of anaphylaxis were reported. Table 3: Adverse Reactions Reported for ELOCTATE (N=164) MedDRA System Organ Class MedDRA Preferred Term Number of Subjects n (%) General disorders and administration site conditions Malaise 2 (1.2) Chest pain 1 (0.6) Feeling cold 1 (0.6) Feeling hot 1 (0.6) Nervous systemdisorders Dizziness 1 (0.6) Dysgeusia 1 (0.6) Headache 1 (0.6) Musculoskeletaldisorders Arthralgia 2 (1.2) Joint swelling 1 (0.6) Myalgia 1 (0.6) Gastrointestinaldisorders Abdominal pain, lower 1 (0.6) Abdominal pain, upper 1 (0.6) Vascular disorders * Angiopathy 1 (0.6) Hypertension 1 (0.6) Cardiac disorders Bradycardia 1 (0.6) Injury, poisoning, and procedural complications Procedural hypotension 1 (0.6) Respiratory, thoracic, and mediastinal disorders Cough 1 (0.6) Skin and subcutaneous tissue disorders Rash 1 (0.6) *Investigator term: vascular pain after injection of study drug Immunogenicity Clinical trial subjects were monitored for neutralizing antibodies to Factor VIII. No subjects developed confirmed, neutralizing antibodies to Factor VIII. One 25 year old subject had a transient, positive, neutralizing antibody of 0.73 BU at week 14, which was not confirmed upon repeat testing 18 days later and thereafter. The detection of antibodies that are reactive to Factor VIII is highly dependent on many factors, including: the sensitivity and specificity of the assay, sample handling, timing of sample collection, concomitant medications and underlying disease. DRUG INTERACTIONS No information provided.

SIDE EFFECTS The most frequently reported adverse reactions ( ≥ 0.5%) were injection site reactions, increased hepatic enzymes, and pyrexia. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. During the clinical development of Novoeight®, 214 male previously treated patients (PTPs; exposed to a factor VIII-containing product for ≥ 150 days) with severe hemophilia A (factor VIII level ≤ 1%) received at least one dose of Novoeight® as part of either routine prophylaxis, on-demand treatment of bleeding episodes, perioperative management of major and minor surgical, dental, or other invasive procedures, or pharmacokinetic evaluation of Novoeight®. Thirty-one subjects (14%) were < 6 years of age, 32 (15%) were 6 to < 12 years of age, 16 (7%) were adolescents (12 to < 16 years of age), and 135 (63%) were adults (16 years of age and older). The subjects received a total of 33,272 injections with a median of 127 injections of Novoeight® (range 1-442) per subject, and had a total of 32,929 exposure days during prevention and treatment of bleeds. The most frequently reported adverse reactions in previously treated patients was injection site reactions (2.3%), increased hepatic enzymes (1.4%), and pyrexia (0.9%). Immunogenicity Subjects were monitored for neutralizing antibodies to factor VIII and binding antibodies to CHO and murine protein. No subjects developed confirmed neutralizing antibodies to factor VIII. One twenty-two month old child had a positive neutralizing antibody to factor VIII of 1.3 [BU] in the Bethesda assay after 15 exposure days that was not confirmed when checked after 20 exposure days. In vivo recovery was normal for this child and no clinical adverse findings were observed. No patients developed de novo anti-murine antibodies. Nineteen subjects were positive for anti-Chinese hamster ovary (CHO) cell protein antibodies. Two of these subjects changed from anti-CHO negative to anti-CHO positive and 6 subjects changed from anti-CHO positive to anti-CHO negative. The remaining 11 subjects were either positive throughout the trials (n=6), negative at baseline and end-of trial but with transient positive samples (n=2), or positive at baseline and end-of trial but with negative samples in between (n=3). No clinical adverse findings were observed in any of these subjects. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. DRUG INTERACTIONS No information provided.

SIDE EFFECTS The most frequently reported adverse reactions in clinical trials ( ≥ 3%) were headache, pyrexia, and pruritus (see Table 3). Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety profile of KOVALTRY was evaluated in 193 previously treated patients (PTPs) (inclusive of 51 pediatric patients < 12 years of age) with at least three months of exposure to KOVALTRY. The safety analysis was done using a pooled database from three multi-center, prospective, open-label clinical studies. The median time on study for patients ≥ 12 years of age was 372 days with a median of 159 exposure days (EDs). The median time on study for patients < 12 years of age was 182 days with a median of 73 EDs. Subjects who received KOVALTRY for perioperative management (n=5) with treatment period of 2 to 3 weeks and those who received single doses of KOVALTRY for PK studies (n=6) were excluded from safety analysis. Table 3 lists the adverse reactions reported during clinical studies. The frequency, type, and severity of adverse reactions in children are similar to those in adults. Table 3: Adverse Reactions in PTPs (N=193) MedDRA Primary System Organ Class Preferred term Frequency N (%) Blood and the Lymphatic System Disorders Lymphadenopathy 2 (1.0%) Cardiac Disorders Palpitation 2 (1.0%) Sinus tachycardia 2 (1.0%) Gastrointestinal Disorders Abdominal pain 4 (2.1%) Abdominal discomfort 3 (1.6%) Dyspepsia 4 (2.1%) General Disorders and Administration Site Conditions Pyrexia 8 (4.1%) Chest discomfort 2 (1.0%) Injection site reactionsa 5 (2.6%) Immune System Disorders Hypersensitivity 1 (0.5%) Nervous System Disorders Dizziness 2 (1.0%) Dysgeusia Headache 1 (0.5%) 14 (7.3%) Psychiatric Disorders Insomnia. 5 (2.6%) Skin and Subcutaneous Tissue Disorders Dermatitis allergic 2 (1.0%) Pruritus 6 (3.1%) Rashb 5 (2.6%) Urticaria 1 (0.5%) Vascular disorders Flushing 1 (0.5%) aIncludes injection site extravasation and hematoma, infusion site pain, pruritus, and swelling bIncludes rash, rash erythematous, and rash pruritic Immunogenicity All clinical trial subjects were monitored for neutralizing antibodies (inhibitors) to Factor VIII by the modified Bethesda assay using blood samples obtained prior to the first infusion of KOVALTRY, at defined intervals during the studies and at the completion visit. Clinical trials (Phases 1 through 3) with KOVALTRY evaluated a total of 204 pediatric and adult patients diagnosed with severe hemophilia A (Factor VIII < 1%) with previous exposure to Factor VIII concentrates ≥ 50 EDs, and no history of inhibitors. In the completed studies, no PTP developed neutralizing antibodies to Factor VIII. In an ongoing extension study, a 13 year old PTP had a titer of 0.6 BU after 550 EDs concurrent with an acute infection and positive IgG anticardiolipin antibodies. The Factor VIII recovery was 2.2 IU/dL per IU/kg, annualized bleeding rate (ABR) was zero, and no change in therapy was required. In an actively enrolling clinical trial in PUPs, 6 of 14 treated subjects (42.9% with a 95% Confidence Interval of 17.7-71.1%) developed an inhibitor. Of these, 3 subjects (21.4%) had high titer inhibitors, and 3 subjects (21.4%) had transient low titer inhibitors for which no change in therapy was required. The detection of antibody formation is dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, it may be misleading to compare the incidence of antibodies to KOVALTRY with the incidence of antibodies to other products. DRUG INTERACTIONS No information provided.

SIDE EFFECTS During the clinical studies conducted in the previously treated patient group, there were 13 infusion related minor adverse reactions reported out of 10,446 infusions (0.12%). One patient experienced flushing and nausea during his first infusion which abated on decreasing the infusion rate. A second patient experienced mild fatigue during and following one infusion and a third patient had a series of eleven nose bleeds with a periodicity associated with the infusions. The protein in greatest concentration in RECOMBINATE (antihemophilic factor (recombinant)) rAHF is Albumin (Human). Reactions associated with intravenous administration of albumin are extremely rare, although nausea, fever, chills or urticaria have been reported. Other allergic reactions could theoretically be encountered in the use of this Antihemophilic Factor preparation. See Information for Patients. DRUG INTERACTIONS No information provided.

SIDE EFFECTS The most serious adverse reactions are systemic hypersensitivity reactions including bronchospastic reactions and/or hypotension and anaphylaxis and the development of high-titer inhibitors necessitating alternative treatments to AHF. The most common adverse reactions observed in clinical trials (frequency ≥ 4% of patients) are inhibitor formation in previously untreated patients (PUPs) and minimally treated patients (MTPs), skin-related hypersensitivity reactions (e.g., rash, pruritus), infusion site reactions (e.g., inflammation, pain), and central venous access device (CVAD) line-associated infections in patients requiring a CVAD for intravenous administration. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. Previously Treated Patients (PTPs) During the clinical studies conducted in PTPs, there were 24 adverse reactions reported in the course of 24,936 infusions. Adverse reactions reported by ≥ 4% of the patients are listed in Table 3 below. Table 3 : Adverse Reactions (AR) in Previously Treated Patients (PTPs) with Frequency of ≥ 4% MedDRA Primary SOC Preferred Term Total No. of Patients: 73 No. of Patients with AR (%) Total No. of Infusions: 24,936 AR per Infusion (%) Skin and Subcutaneous Tissue Disorders Rash, pruritus 6 (8.2%) 0.02 General Disorders and Administration Site Conditions Infusion site reactions 3 (4.1%) 0.01 SOC = System Organ Class Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs) In clinical studies with pediatric PUPs and MTPs, there were 29 adverse reactions reported in the course of 9,389 infusions. Adverse reactions reported by ≥ 4% of the patients are listed in Table 4 below. Table 4 : Adverse Reactions (AR) in Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs) with Frequency of ≥ 4% (Age Range 2-27 months) MedDRA Primary SOC Preferred Term Total No. of patients: 61 No. of Patients with AR (%) Total No. of Infusions: 9,389 AR per Infusion (%) Skin and Subcutaneous Tissue Disorders Rash, pruritus, urticaria 10 (16.4) 0.01 Blood and Lymphatic System Disorders Factor VIII inhibition 9 (15)1 N/A General Disorders and Administration Site Conditions Infusion site reactions 4 (6.6) 0.04 SOC = System Organ Class 1 Denominator for de novo inhibitors is N=60, since one patient had a pre-existing inhibitor. Minimally Treated Patients (MTPs) in the Joint Outcome Study In the Joint Outcome Study with pediatric MTPs treated with routine prophylaxis or episodic enhanced treatment for 5.5 years, 46 of the 65 randomized patients experienced adverse events over the study duration. Adverse events were not assessed for their relationship with Kogenate FS. Table 5 : Adverse Events (AE) in MTPs in the Joint Outcome Study (Age Range 0-6 years) MedDRA Primary SOC Preferred Term Total No. of Prophylaxis Arm Patients: 32 No. of Patients with AE (%) Total No. of Enhanced Episodic Arm Patients: 33 No. of Patients with AE (%) Surgical and Medical Procedures Central venous catheterization, Catheter removal 19 (59) 181(55) Infections and Infestations Central line infection 6 (19) 6 (18) General Disorders and Administration Site Conditions Pyrexia 1 (3) 4 (12) SOC = System Organ Class 1 Three patients from the enhanced episodic arm had catheter removal. Immunogenicity In clinical studies with 73 PTPs (defined as having more than 100 exposure days), one patient had a pre-existing inhibitor. In the other 72 patients, followed over 4 years, no de novo inhibitors were observed. In clinical studies with pediatric PUPs and MTPs, inhibitor development was observed in 9 out of 60 patients (15%), 6 were high titer1 ( > 5BU) and 3 were low-titer inhibitors. Inhibitors were detected at a median number of 7 exposure days (range 2 to 16 exposure days). In the Joint Outcome Study with Kogenate FS,5 de novo inhibitor development was observed in 8 of 64 patients with negative baseline values (12.5%), 2 patients developed high titer1 ( > 5 BU) and were withdrawn from the study. Six patients developed low-titer inhibitors. Inhibitors were detected at a median number of 44 exposure days (range 5 to 151 exposure days). Post-Marketing Experience The following adverse reactions have been identified during post approval use of Kogenate FS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Among patients treated with Kogenate FS, cases of serious allergic/hypersensitivity reactions (which may include facial swelling, flushing, hives, blood pressure decrease, nausea, rash, restlessness, shortness of breath, tachycardia, tightness of the chest, tingling, urticaria, vomiting) have been reported, particularly in very young patients or patients who have previously reacted to other factor VIII concentrates. The following table represents the post-marketing adverse reactions as MedDRA Preferred Terms. Table 6 Post-Marketing Experience MedDRA Primary SOC Preferred Term Immune System Disorders Anaphylactic reaction, other hypersensitivity reactions Nervous System Disorders Dysgeusia SOC = System Organ Class DRUG INTERACTIONS None known.

SIDE EFFECTS During the clinical studies conducted in previously treated patients (PTPs), 109 adverse events were reported in the course of 4160 infusions (2.6%). Only 13 events were reported by the investigator as at least remotely related to study drug. Another 7 events were nonassessable. Thus 20 events in 11 patients were considered to be either nonassessable or at least remotely related to Helixate FS (antihemophilic factor (recombinant)) administration, for an incidence of 0.5% relative to the number of infusions administered. Events that were at least remotely drug-related included: local injection site reactions (2), dizziness (2), rash (2), unusual taste in the mouth (1), mild increase in blood pressure (1), pruritus (1), depersonalization (1), nausea (1), and rhinitis (1). No FVIII inhibitors have developed in the 72 PTPs with severe hemophilia A who have received Helixate FS (antihemophilic factor (recombinant)) for a mean of 54 exposure days. In clinical studies with previously untreated patients (PUPs) and minimally treated (MTP) pediatric patients, 18 adverse events were reported by the clinical investigators as at least possibly related to the study drug including the expected complication of inhibitor development in 8 patients (included in the 10 patients discussed under CLINICAL PHARMACOLOGY), a forearm bleed following venipuncture, constipation, adenopathy, rash, anemia and pallor in one inhibitor patient with gastroenteritis, and serous otitis media. Post-marketing experience The following events are principally derived from post-marketing experience and publications,14 and accurate rate estimates are generally not possible. Among patients treated with its predecessor product HELIXATE, very rare cases of serious allergic reactions and anaphylactic reactions have been reported, particularly in very young patients or patients who had previously reacted to other FVIII concentrates. Individual cases of hypotension have been very rarely reported. Rare cases of urticaria have also been reported. Although such serious reactions have not been reported with the use of Helixate FS (antihemophilic factor (recombinant)) , it is likely that these may also occur. Rare cases of dyspnea have been reported with Helixate FS (antihemophilic factor (recombinant)) . DRUG INTERACTIONS No information provided. REFERENCES 14. Pernod G, Armari C, Barro C, et al: Anaphylaxis following the use of a plasma-derived immunopurified Monoclate-P®, and the recombinant Recombinate® and Kogenate® factor VIII: a therapeutic challenge. Haemophilia 5(2):143-4, 1999.

SIDE EFFECTS Products of this type are known to cause allergic reactions, mild chills, nausea or stinging at the infusion site. In some cases, inhibitors of FVIII may occur. DRUG INTERACTIONS No information provided.

SIDE EFFECTS Allergic-type reactions may result from the administration of Antihemophilic Factor (Human) preparations.10,11 Ten adverse reactions related to 7 infusions were observed during a total of 1053 infusions performed during the clinical study of Koate (antihemophilic factor) -DVI, for a frequency of 0.7% infusions associated with adverse reactions. All reactions were mild and included tingling in the arm, ear, and face, blurred vision, headache, nausea, stomach ache, and jittery feeling.2 DRUG INTERACTIONS No information provided. REFERENCES 2. Data on file. 10. Eyster ME, Bowman HS, Haverstick JN: Adverse reactions to factor VIII infusions. [letter] Ann Intern Med 87(2):248, 1977. 11. Prager D, Djerassi I, Eyster ME, et al: Pennsylvania state-wide hemophilia program: summary of immediate reactions with the use of factor VIII and factor IX concentrate. Blood 53(5):1012–3, 1979.

SIDE EFFECTS Serious adverse drug reactions (ADRs) observed in patients receiving ALPHANATE include anaphylaxis/hypersensitivity reactions. Thromboembolic events also have been observed in patients receiving ALPHANATE for VWD [see WARNINGS AND PRECAUTIONS]. Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse drug reaction (ADR) rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. Hemophilia A In a prospective clinical study with ALPHANATE, 23 subjects were exposed to 1217 infusions (median=42, range 2-160). The total number of exposure days was 1133, and the total number of months on study across all subjects was 234 (19.5 subject years). No ADRs or inhibitors to FVIII were reported during the study. Von Willebr And Disease In the prospective clinical study of ALPHANATE [using both ALPHANATE Solvent Detergent (A-SD, a previous generation product) and ALPHANATE Solvent Detergent/Heat Treated (A-SD/HT, the current generation product)] in subjects with von Willebrand Disease, ADRs occurred in 5 of 36 subjects (13.9%) treated with ALPHANATE. Sixty-one total ADRs were reported in 204 infusions. The majority of ADRs were rated as mild (55 of 61 [90.2%]). Six ADRs (9.8%) were rated as moderate. No reactions rated as serious were reported. The adverse drug reaction grading scale is defined as follows: Mild: the event was noted but the administration of the compound was not interrupted; the event resolved spontaneously or no treatment was required beyond administration of nonprescription analgesics. Moderate: the administration of the compound was not necessarily interrupted; the event required momentary treatment with prescription drugs and produced no sequelae. Overall, the proportion of infusions associated with ADRs was 14 of 204 infusions (6.9%). The most common ADRs reported ( > 1% of infusions) were pruritus, headache, backpain, paresthesia, respiratory distress, facial edema, pain, rash, and chills. One incident of pulmonary embolism was reported that was considered to have a possible relationship to the product. This subject received a dose of 60 IU VWF:RCo/kg body weight and the FVIII:C level achieved was 290%. In the retrospective study conducted to determine the efficacy and safety of ALPHANATE (A-SD/ HT) in a surgical or invasive procedure setting as perioperative prophylaxis against excessive bleeding, [see Clinical Studies], 3 out of 39 subjects (7.7%) experienced 6 adverse drug reactions. Four were considered mild and 2 were considered moderate. No subject discontinued their treatment due to an adverse drug reaction. The adverse drug reactions were pruritus, paresthesia (2 events) and hemorrhage (all considered mild), and one event each of moderate hematocrit decrease and orthostatic hypotension. One adverse drug reaction (pain) related to the treatment with heat-treated ALPHANATE (A-SD/ HT) was reported in the four pediatric subjects with von Willebrand Disease during the course of the prospective study and in none of the five pediatric subjects in the retrospective clinical study. Post-Marketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most common post-marketing ADRs reported include allergic/hypersensitivity reactions, nausea, fever, joint pain, fatigue, and infusion site pain. DRUG INTERACTIONS No information provided.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions Allergic-type hypersensitivity reactions, including anaphylaxis, are possible with XYNTHA. Inform patients of the early signs or symptoms of hypersensitivity reactions (including hives [rash with itching], generalized urticaria, chest tightness, wheezing, and hypotension) and anaphylaxis. Discontinue XYNTHA if hypersensitivity symptoms occur and administer appropriate emergency treatment. XYNTHA contains trace amounts of hamster proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. Neutralizing Antibodies Inhibitors have been reported following administration of XYNTHA. Monitor patients for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures factor VIII inhibitor concentration to determine if a factor VIII inhibitor is present [see Monitoring Laboratory Tests].4,5,6,7,8,9,10,11,12 Monitoring Laboratory Tests Use individual factor VIII values for recovery and, if clinically indicated, other pharmacokinetic characteristics to guide dosing and administration. Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm that adequate factor VIII levels have been achieved and are maintained, when clinically indicated [see DOSAGE AND ADMINISTRATION]. Monitor for development of factor VIII inhibitors. Perform assay to determine if factor VIII inhibitor is present when expected factor VIII activity plasma levels are not attained, or when bleeding is not controlled with the expected dose of XYNTHA. Use Bethesda Units (BU) to titer inhibitors. Patient Counseling Information Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Advise patients to report any adverse reactions or problems that concern them when taking XYNTHA to their healthcare provider. Allergic-type hypersensitivity reactions are possible. Discuss the early signs of hypersensitivity reactions (including hives [rash with itching]), generalized urticaria, tightness of the chest, wheezing, hypotension) and anaphylaxis. Advise patients to discontinue use of the product, call their healthcare provider, and go to the emergency department if these symptoms occur. Advise patients to contact their healthcare provider if they experience a lack of a clinical response to factor VIII replacement therapy, as this may be a manifestation of an inhibitor. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy, or if they are breastfeeding. Advise patients to consult their healthcare provider prior to travel and to bring an adequate supply of XYNTHA, based on their current regimen, for anticipated treatment when traveling. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility No studies have been conducted with XYNTHA to assess its mutagenic or carcinogenic potential. XYNTHA has been shown to be comparable to the predecessor product with respect to its biochemical and physicochemical properties, as well as its nonclinical in vivo pharmacology and toxicology. By inference, predecessor product and XYNTHA would be expected to have equivalent mutagenic and carcinogenic potential. The predecessor product has been shown to be nongenotoxic in the mouse micronucleus assay. No studies have been conducted in animals to assess impairment of fertility or fetal development. Use In Specific Populations Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with XYNTHA. It is not known whether XYNTHA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. XYNTHA should be given to a pregnant woman only if clinically indicated. Labor And Delivery There is no information available on the effect of factor VIII replacement therapy on labor and delivery. XYNTHA should be used only if clinically indicated. Nursing Mothers It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if XYNTHA is administered to nursing mothers. XYNTHA should be given to nursing mothers only if clinically indicated. Pediatric Use In the completed open label safety and efficacy study of XYNTHA (n=94), 17 adolescent subjects 12 to < 16 years of age with severe or moderately severe hemophilia A (FVIII:C ≤ 2%), who were previously treated with at least 150 EDs to FVIII products, received XYNTHA for on-demand and follow-up treatment. The median dose per infusion was 47 IU/kg (min–max: 24–74) and the median exposure per subject was 6 days (min–max: 1–26). Of the 17 subjects < 16 yrs of age who received at least 1 dose of XYNTHA, 10 subjects had bleeding episodes during the study. Among the 10 subjects with response assessments, a total of 66 bleeding episodes were treated with on-demand infusions of XYNTHA. The majority of the bleeding episodes (63/66 or 95.5%) resolved with 1 or 2 infusions. Thirty-eight (38) of 66 bleeding episodes (57.6%) were rated excellent or good in their response to initial treatment, 24 (36.4%) were rated as moderate and 4 (6.1%) were not rated. Additional data are available from a safety and efficacy study of XYNTHA in children < 6 years of age with moderately severe or severe hemophilia A (FVIII:C ≤ 2%) and with at least 20 prior EDs to FVIII products. In this study subjects received XYNTHA for on-demand and follow-up treatment of bleeding episodes. The median dose per infusion was 28 IU/kg and the median exposure per subject was 16 days. Of the 27 subjects < 6 years of age who received at least 1 dose of XYNTHA, 25 had bleeding episodes during the study. Among the 24 subjects with response assessments there were 493 bleeds. The majority of the bleeding episodes (462/493 or 93.7%) resolved with 1 or 2 infusions. Subjects rated the outcomes of infusions on a pre-specified four (4) point hemostatic efficacy scale. Of 493 bleeding episodes treated with XYNTHA, 468 (94.9%) were rated excellent or good in their response to initial treatment and 22 (4.5%) were rated as moderate. In comparison to the pharmacokinetic parameters reported in adults, children have shorter half-lives, larger volumes of distribution and lower recovery of factor VIII after XYNTHA administration. The clearance (based on per kg body weight) is approximately 40% higher in children. Higher or more frequent doses may be required to account for the observed differences in pharmacokinetic parameters. [see CLINICAL PHARMACOLOGY] Geriatric Use Clinical studies of XYNTHA did not include subjects aged 65 and over. In general, dose selection for an elderly patient should be individualized. REFERENCES 4. Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII and factor IX inhibitors in hemophiliacs. Lancet. 1992;339:594–598. 5. Lusher J, Arkin S, Abildgaard CF, Schwartz RS, the Kogenate PUP Study Group. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. N Engl J Med. 1993;328:453–459. 6. Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor VIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood. 1994;83(9):2428–2435. 7. Kessler C, Sachse K. Factor VIII:C inhibitor associated with monoclonal-antibody purified FVIII concentrate. Lancet. 1990;335:1403. 8. Schwartz RS, Abildgaard CF, Aledort LM, et al. Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med. 1990;323:1800–1805. 9. White GC II, Courter S, Bray GL, et al. A multicenter study of recombinant factor VIII (Recombinate™) in previously treated patients with hemophilia A. Thromb Haemost. 1997;77(4):660–667. 10. Gruppo R, Chen H, Schroth P, et al. Safety and immunogenicity of recombinant factor VIII (Recombinate™) in previously untreated patients: A 7.3 year update. Haemophilia. 1998;4:228 (Abstract No. 291, XXIII Congress of the WFH, The Hague). 11. Scharrer I, Bray GL, Neutzling O. Incidence of inhibitors in haemophilia A patients - a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Haemophilia. 1999;5:145–154. 12. Abshire TC, Brackmann HH, Scharrer I, et al. Sucrose formulated recombinant human antihemophilic Factor VIII is safe and efficacious for treatment of hemophilia A in home therapy: Results of a multicenter, international, clinical investigation. Thromb Haemost. 2000;83(6):811–816.

WARNINGS As with any intravenous protein product, allergic type hypersensitivity reactions are possible. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physicians if these symptoms occur. PRECAUTIONS General Activity-neutralizing antibodies (inhibitors) have been detected in patients receiving factor VIII-containing products. Low-titer inhibitors are common in previously untreated patients and in previously treated patients on factor VIII products, as are high-titer inhibitors in previously untreated patients. High-titer inhibitors, which are generally rare in previously treated patients, have been reported in previously treated patients on ReFacto (antihemophilic factor) . As with all coagulation factor VIII products, patients should be monitored for the development of inhibitors that should be titrated in Bethesda Units using appropriate biological testing. Reports of less than expected or lack of effect following infusion of ReFacto (antihemophilic factor) , mainly in prophylaxis patients, have been received during the clinical trials and in the post-marketing setting. The reported less than expected or lack of effect has been described as unexpected bleeding into target joints, bleeding into new joints or a subjective feeling by the patient of new onset bleeding. Less than expected or lack of effect and/or low factor VIII recovery has been reported in patients with inhibitors but also in patients who had no evidence of inhibitors. When switching to ReFacto (antihemophilic factor) it is important to closely monitor each patient's clinical hemostatic response and plasma FVIII:C activity following administration of the product and to titrate the dose accordingly in order to ensure an adequate therapeutic response (see DOSAGE AND ADMINISTRATION). Monitoring plasma FVIII:C activity is particularly important in the setting of surgical prophylaxis and major bleeds. Formation of Antibodies to Mouse and Hamster Protein As Antihemophilic Factor (Recombinant), ReFacto (antihemophilic factor) contains trace amounts of mouse protein (maximum of 5 ng/1000 IU) and hamster protein (maximum of 30 ng/1000 IU), the remote possibility exists that patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. Carcinogenicity, Mutagenicity, Impairment of Fertility ReFacto® Antihemophilic Factor (Recombinant) has been shown to be nonmutagenic in the mouse micronucleus assay. No other mutagenicity studies and no investigations on carcinogenesis or impairment of fertility have been conducted. Pregnancy Category C Animal reproduction and lactation studies have not been conducted with ReFacto® Antihemophilic Factor (Recombinant). It is not known whether ReFacto (antihemophilic factor) can affect reproductive capacity or cause fetal harm when given to pregnant women. ReFacto (antihemophilic factor) should be administered to pregnant and lactating women only if clearly indicated. Pediatric Use ReFacto® Antihemophilic Factor (Recombinant) is appropriate for use in children of all ages, including newborns. Safety and efficacy studies have been performed both in previously treated children and adolescents (n=31, ages 5-18 years) and in previously untreated neonates, infants, and children (n=101, ages < 1-52 months) (see CLINICAL PHARMACOLOGY and PRECAUTIONS). Geriatric Use Clinical studies of ReFacto (antihemophilic factor) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. As with any patient receiving ReFacto (antihemophilic factor) , dose selection for an elderly patient should be individualized.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions can occur with OBIZUR. OBIZUR contains trace amounts of hamster proteins. Early signs of allergic reactions, which can progress to anaphylaxis, include angioedema, chest-tightness, dyspnea, hypotension, wheezing, urticaria, and pruritus. Immediately discontinue administration and initiate appropriate treatment if allergic or anaphylactic-type reactions occur. Inhibitory Antibodies Inhibitory antibodies to OBIZUR have occurred. Monitor patients for the development of antibodies to OBIZUR by appropriate assays [see Monitoring Laboratory Tests]. If the plasma factor VIII level fails to increase as expected, or if bleeding is not controlled after OBIZUR administration, suspect the presence of an anti-porcine factor VIII antibody. If such inhibitory antibodies to anti-porcine factor VIII are suspected and there is a lack of clinical response, consider other therapeutic options. Monitoring Laboratory Tests Perform one-stage clotting assay to confirm that adequate factor VIII levels have been achieved and maintained [see DOSAGE AND ADMINISTRATION]. Monitor factor VIII activity 30 minutes and 3 hours after initial dose. Monitor factor VIII activity 30 minutes after subsequent doses. Monitor the development of inhibitory antibodies to OBIZUR. Perform a Nijmegen Bethesda inhibitor assay if expected plasma factor VIII activity levels are not attained or if bleeding is not controlled with the expected dose of OBIZUR. Use Bethesda Units (BU) to report inhibitor levels. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term studies in animals to evaluate the carcinogenic potential of OBIZUR, or studies to determine genotoxicity and the effects of OBIZUR on fertility, have not been performed. Use In Specific Populations Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with OBIZUR. It is also not known whether OBIZUR can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. OBIZUR should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if OBIZUR is administered to nursing mothers. Pediatric Use The safety and efficacy of OBIZUR have not been established in pediatric patients. Geriatric Use Of the 29 subjects within the trial, the average age was 70 years of age. Nineteen subjects were 65 years of age or older. Clinical studies suggest that OBIZUR is safe and effective in the adult population [see ADVERSE REACTIONS and Clinical Studies]. While no differences were observed between geriatric and adult responses to OBIZUR, these findings are inconclusive given the small number of subjects enrolled in either group. Dose adjustments in the geriatric population have not been studied. Specific hazards associated with the concomitant use of OBIZUR with other drugs in the elderly population have not been studied in the clinical trial.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions are possible with ADYNOVATE. Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with other recombinant antihemophilic factor VIII products, including the parent molecule, ADVATE. Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur. Neutralizing Antibodies Formation of neutralizing antibodies (inhibitors) to factor VIII can occur following administration of ADYNOVATE. Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected, or if bleeding is not controlled with expected dose. Monitoring Laboratory Tests Monitor plasma factor VIII activity by performing a validated one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained [see DOSAGE AND ADMINISTRATION]. Monitor for the development of factor VIII inhibitors. Perform the Bethesda inhibitor assay to determine if factor VIII inhibitor is present. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with the expected dose of ADYNOVATE, use Bethesda Units (BU) to determine inhibitor levels. Patient Counseling Information Advise patients to: Read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use). Call their healthcare provider or go to the emergency department right away if a hypersensitivity reaction occurs. Early signs of hypersensitivity reactions may include rash, hives, itching, facial swelling, tightness of the chest, and wheezing. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment. Contact their healthcare provider or treatment facility for further treatment and/or assessment if they experience a lack of a clinical response to factor VIII therapy because this may be a sign of inhibitor development. Advise patients to consult with their physicians or healthcare provider prior to travel. While traveling, advise patients to bring an adequate supply of ADYNOVATE based on their current regimen of treatment. To enroll in the confidential, industry-wide Patient Notification System, call 1-888-873-2838. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term studies in animals to evaluate the carcinogenic potential of ADYNOVATE or studies to determine the effects of ADYNOVATE on genotoxicity or fertility have not been performed. Use In Specific Populations Pregnancy Risk Summary There are no data with ADYNOVATE use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with ADYNOVATE. It is unknown whether ADYNOVATE can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ADYNOVATE should be given to a pregnant woman only if clearly needed. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Lactation Risk Summary There is no information regarding the presence of ADYNOVATE in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ADYNOVATE and any potential adverse effects on the breastfed infant from ADYNOVATE or from the underlying maternal condition. Pediatric Use The safety, efficacy, or pharmacokinetic profiles of ADYNOVATE have not been established in pediatric patients less than 12 years old. In the clinical trial, 25 adolescents aged 12 to less than 18 were included in the analysis. The safety, efficacy, and PK profile were comparable between adolescents and adults [see CLINICAL PHARMACOLOGY and Clinical Studies]. Geriatric Use Clinical studies of ADYNOVATE did not include subjects aged 65 and over.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, are possible with ELOCTATE. Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur. Neutralizing Antibodies Formation of neutralizing antibodies (inhibitors) to Factor VIII can occur following administration of ELOCTATE. Monitor all patients for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests. If the plasma Factor VIII level fails to increase as expected or if bleeding is not controlled after ELOCTATE administration, suspect the presence of an inhibitor (neutralizing antibody). [see Monitoring Laboratory Tests] Monitoring Laboratory Tests Monitor plasma Factor VIII activity by performing a validated test (e.g., one stage clotting assay), to confirm that adequate Factor VIII levels have been achieved and maintained. [see DOSAGE AND ADMINISTRATION] Monitor for the development of Factor VIII inhibitors. Perform a Bethesda inhibitor assay if expected Factor VIII plasma levels are not attained, or if bleeding is not controlled with the expected dose of ELOCTATE. Use Bethesda Units (BU) to report inhibitor levels. Patient Counseling Information Advise the patients to: Read the FDA approved patient labeling (PATIENT INFORMATION and Instructions for Use) Call their healthcare provider or go to the emergency department right away if a hypersensitivity reaction occurs. Early signs of hypersensitivity reactions may include rash, hives, itching, facial swelling, tightness of the chest, and wheezing. Report any adverse reactions or problems following ELOCTATE administration to their healthcare provider. Contact their healthcare provider or treatment facility for further treatment and/or assessment if they experience a lack of a clinical response to Factor VIII therapy because this may be a sign of inhibitor development. Use In Specific Populations Pregnancy Pregnancy Category C Animal reproductive studies have not been conducted with ELOCTATE. It is not known whether or not ELOCTATE can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ELOCTATE should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether or not ELOCTATE is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised when ELOCTATE is administered to a nursing woman. Pediatric Use Pharmacokinetic studies in children have demonstrated a shorter half-life and lower recovery of Factor VIII compared to adults. Because clearance (based on per kg body weight) has been shown to be significantly higher in the younger, pediatric population (2 to 5 years of age), higher and/or more frequent dosing based on body weight may be needed. [see CLINICAL PHARMACOLOGY] Safety and efficacy studies have been performed in 56 previously treated, pediatric patients < 18 years of age who received at least one dose of ELOCTATE as part of routine prophylaxis, on-demand treatment of bleeding episodes, or perioperative management. Adolescent subjects were enrolled in the adult and adolescent safety and efficacy trial, and subjects < 12 were enrolled in an ongoing pediatric trial. Twelve subjects (21%) were < 6 years of age, 31 (55%) subjects were 6 to < 12 years of age, and 13 subjects (23%) were adolescents (12 to < 18 years of age). Interim pharmacokinetic data from a pediatric study of the 38 subjects < 12 years of age showed that no dose adjustment had been required for patients ≥ 6 years old. Children age 2 to 5 years had a shorter half-life and higher clearance (adjusted for body weight); therefore, a higher dose or more frequent dosing may be needed in this age group. [see CLINICAL PHARMACOLOGY] Geriatric Use Clinical studies of ELOCTATE did not include sufficient numbers of subjects aged 65 and over to determine whether or not they respond differently from younger subjects.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, are possible with Novoeight®. Novoeight® contains trace amounts of hamster proteins. Patients treated with this product may develop hypersen­sitivity to these non-human mammalian proteins. Early signs of hypersensitivity reactions that can progress to anaphylaxis include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. Immediately discontinue administration and initiate appropriate treatment if allergic- or anaphylactic-type reactions occur. Neutralizing Antibodies Formation of neutralizing antibodies (inhibitors) to factor VIII can occur following administration of Novoeight®. Monitor all patients for the development of inhibitors by appropriate clinical observation and laboratory testing. If the expected plasma levels of factor VIII activity are not attained, or if bleeding is not controlled with an appropriate dose, perform testing for factor VIII inhibitors. Monitoring Laboratory Tests Monitor plasma factor VIII activity levels by the one-stage clotting assay or the chromogenic substrate assay to confirm that adequate factor VIII levels have been achieved and maintained, when clinically indicated. [See DOSAGE AND ADMINISTRATION] Perform assay to determine if factor VIII inhibitor is present if expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with the expected dose of Novoeight®. Determine inhibitor levels in Bethesda Units. Patient Counseling Information Advise patients to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use). Allergic-type hypersensitivity reactions or anaphylaxis are possible with use of Novoeight®. Inform patients of the early signs of hypersensitivity reactions including rash, hives, itching, facial swelling, tightness of the chest and wheezing. Advise patients to discontinue use of Novoeight® immediately and contact their physician, and go to the emergency department if these symptoms occur. Advise patients to contact their physician or treatment facility for further treatment and/or assessment if they experience a lack of a clinical response to factor VIII replacement therapy, as this may be a manifestation of an inhibitor. Advise patients to consult with their healthcare provider prior to traveling. While traveling, patients should be advised to bring an adequate supply of Novoeight® based on their current treatment regimen. Advise patients to follow the recommendations regarding proper sharps disposal provided in the FDA-approved Instructions for Use. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term studies in animals to evaluate the carcinogenic potential of Novoeight®, or studies to determine the effects of Novoeight® on genotoxicity or fertility have not been performed. An assessment of the carcinogenic potential of Novoeight® was completed, and no carcinogenic risk from product use has been identified. Use In Specific Populations Pregnancy Risk Summary As hemophilia mainly affects males, there are no adequate and well-controlled studies using Novoeight® in pregnant women to determine whether there is a drug-associated risk. Animal reproduction studies have not been conducted with Novoeight®. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. There is no reliable data on the incidences specific to the hemophilia A population. Lactation Risk Summary There is no information regarding the presence of Novoeight® in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Novoeight® and any potential adverse effects on the breastfed infant from Novoeight® or from the underlying maternal condition. Pediatric Use Children have shorter half–life and lower recovery of factor VIII than adults. Because clearance (based on per kg body weight) has been demonstrated to be higher in the pediatric population, higher or more frequent dosing based on body weight may be needed. [See CLINICAL PHARMACOLOGY] Safety and efficacy studies have been performed in 79 previously treated pediatric patients < 16 years of age. Thirty-one of these subjects (39%) were < 6 years of age, 32 (41%) were 6 to < 12 years of age, and 16 (20%) were adolescents (12 to < 16 years of age). All subjects received preventive treatment every other day or three times weekly at the dose levels described in Table 3. A total of 244 bleeds in 54 subjects were treated with Novoeight®. The majority of the bleeds (91%) were of mild/moderate severity, 41% of the bleeds were spontaneous and 58% of the bleeds were localized in joints. Of these 244 bleeds, 210 (86%) were rated excellent or good in their response to treatment with Novoeight® and 3 (1.2%) were rated as having no response. A total of 222 (91%) of the bleeds were resolved with one or two injections of Novoeight®. Routine prophylactic treatment has been shown to reduce joint bleeding. [See Clinical Studies] Geriatric Use Clinical studies of Novoeight® did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, are possible with KOVALTRY. Early signs of hypersensitivity reactions, which can progress to anaphylaxis, may include chest or throat tightness, dizziness, mild hypotension and nausea. Discontinue KOVALTRY if symptoms occur and seek immediate emergency treatment. KOVALTRY may contain trace amounts of mouse and hamster proteins [see DESCRIPTION]. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. Neutralizing Antibodies Neutralizing antibody (inhibitor) formation can occur following administration of KOVALTRY. Previously untreated patients (PUPs) are at greatest risk for inhibitor development with all Factor VIII products [see ADVERSE REACTIONS]. Carefully monitor patients for the development of Factor VIII inhibitors, using appropriate clinical observations and laboratory tests. If expected plasma Factor VIII activity levels are not attained or if bleeding is not controlled as expected with administered dose, suspect the presence of an inhibitor (neutralizing antibody) [see Monitoring Laboratory Tests]. Cardiovascular Risk Factors Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with Factor VIII. Catheter-Related Infections Catheter-related infections may be observed when KOVALTRY is administered via central venous access devices (CVADs). These infections have not been associated with the product itself. Monitoring Laboratory Tests Monitor plasma Factor VIII activity levels using a validated test to confirm that adequate Factor VIII levels have been achieved and maintained [see DOSAGE AND ADMINISTRATION]. Monitor for development of Factor VIII inhibitors. Perform a Bethesda inhibitor assay if expected Factor VIII plasma levels are not attained or if bleeding is not controlled with the expected dose of KOVALTRY. Use Bethesda Units (BU) to report inhibitor titers. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Hypersensitivity reactions are possible with KOVALTRY [see WARNINGS AND PRECAUTIONS]. Warn patients of the early signs of hypersensitivity reactions (including tightness of the chest or throat, dizziness, mild hypotension and nausea during infusion) which can progress to anaphylaxis. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment with resuscitative measures such as the administration of epinephrine and oxygen. Inhibitor formation may occur at any time in the treatment of a patient with hemophilia A [see WARNINGS AND PRECAUTIONS]. Advise patients to contact their physician or treatment center for further treatment and/or assessment, if they experience a lack of clinical response to Factor VIII replacement therapy, as this may be a manifestation of an inhibitor. Advise patients to discard all equipment, including any unused product, in an appropriate container. Advise patients to consult with their healthcare provider prior to travel. Advise patients to bring an adequate supply of KOVALTRY while traveling based on their current regimen of treatment. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term studies in animals to evaluate the carcinogenic potential of KOVALTRY or other studies to determine the effects of KOVALTRY on fertility have not been performed. KOVALTRY was negative in the modified in-vitro (Mammalian Mutation and Chromosome Aberration Assay with Mouse Lymphoma Cells) genotoxicity test. KOVALTRY is expected to have no mutagenic potential. Use In Specific Populations Pregnancy Risk Summary There are no data with KOVALTRY use in pregnant women to inform on drug-associated risk. Animal reproduction studies have not been conducted using KOVALTRY. It is not known whether KOVALTRY can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. KOVALTRY should be given to a pregnant woman only if clearly needed. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Lactation Risk Summary There is no information regarding the presence of KOVALTRY in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for KOVALTRY and any potential adverse effects on the breastfed infant from KOVALTRY or from the underlying maternal condition. Pediatric Use Safety and efficacy studies with KOVALTRY have been performed in pediatric PTPs. Body weight adjusted clearance of Factor VIII in children ≤ 12 years of age is higher than in adults and adolescents. Consider higher or more frequent dosing in children to account for this difference in clearance [see CLINICAL PHARMACOLOGY]. Geriatric Use Clinical studies with KOVALTRY did not include patients aged 65 and over to determine whether or not they respond differently from younger patients. However, clinical experience with other Factor VIII products has not identified differences between the elderly and younger patients. As with any patient receiving recombinant Factor VIII, dose selection for an elderly patient should be individualized.

WARNINGS None. PRECAUTIONS General Certain components used in the packaging of this product contain natural rubber latex. Identification of the clotting defect as a Factor VIII deficiency is essential before the administration of RECOMBINATE, Antihemophilic Factor (Recombinant) (rAHF) is initiated. No benefit may be expected from this product in treating other deficiencies. The formation of neutralizing antibodies, inhibitors to factor VIII, is a known complication in the management of individuals with hemophilia A. The reported prevalence of these antibodies in patients receiving plasma derived AHF is 10-20%3-7,10-12. These inhibitors are invariably IgG immunoglobulins, the factor VIII procoagulant inhibitory activity of which is expressed as Bethesda Units (B.U.) per mL of plasma or serum3-7. Over the investigational period, none of the 69 previously treated individuals, without an inhibitor at entry into the study, developed an inhibitor. In the previously untreated patient group there were 73 eligible patients with factor VIII levels less than or equal to 2% who received at least one rAHF treatment (median days 100, range 3-821) and who were tested for inhibitor after treatment with RECOMBINATE (antihemophilic factor (recombinant)) rAHF. Of this group, 23 individuals developed detectable inhibitor (median days 10, range 3-69) and of these, 8 patients showed a titer greater than 10 B.U. Patients treated with rAHF should be carefully monitored for the development of antibodies to rAHF by appropriate clinical observations and laboratory tests. Formation of Antibodies to Mouse, Hamster or Bovine Protein As RECOMBINATE (antihemophilic factor (recombinant)) rAHF contains trace amounts of mouse protein (maximum of 0.1 ng/IU rAHF), hamster protein (maximum of 1.5 ng CHO protein/IU rAHF), and bovine protein (maximum of 1 ng BSA/IU rAHF), the remote possibility exists that patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. Laboratory Tests Although dosage can be estimated by the calculations which follow, it is strongly recommended that whenever possible, appropriate laboratory tests be performed on the patient's plasma at suitable intervals to assure that adequate AHF levels have been reached and are maintained. If the patient's plasma AHF fails to reach expected levels or if bleeding is not controlled after adequate dosage, the presence of inhibitor should be suspected. By performing appropriate laboratory procedures, the presence of an inhibitor can be demonstrated and quantified in terms of AHF International Units neutralized by each mL of plasma or by the total estimated plasma volume. If the inhibitor is present at levels less than 10 Bethesda Units per mL, administration of additional AHF may neutralize the inhibitor. Thereafter, the administration of additional AHF International Units should elicit the predicted response. The control of AHF levels by laboratory assay is necessary in this situation. Inhibitor titers above 10 Bethesda Units per mL may make hemostasis control with AHF either impossible or impractical because of the very large dose required. In addition, the inhibitor titer may rise following AHF infusion because of an anamnestic response to the AHF antigen. Carcinogenesis, Mutagenesis, Impairment of Fertility RECOMBINATE (antihemophilic factor (recombinant)) rAHF was tested for mutagenicity at doses considerably exceeding plasma concentrations of rAHF in vitro and at doses up to ten times the expected maximum clinical dose in vivo, and did not cause reverse mutations, chromosomal aberrations, or an increase in micronuclei in bone marrow polychromatic erythrocytes. Long term studies in animals have not been performed to evaluate carcinogenic potential. Pediatric Use RECOMBINATE, Antihemophilic Factor (Recombinant) (rAHF) is appropriate for use in children of all ages, including the newborn. Safety and efficacy studies have been performed in both previously treated (n=23) and previously untreated (n=75) children. (See CLINICAL PHARMACOLOGY and PRECAUTIONS). Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Antihemophilic Factor (Recombinant). It is not known whether Antihemophilic Factor (Recombinant) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Antihemophilic Factor (Recombinant) should be given to a pregnant woman only if clearly needed. REFERENCES 3. Schwarzinger I, Pabinger I, Korninger C, Haschke F, Kundi M, Niessner H, Lechner K: Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates. Am J Hematology 24:241-245, 1987 4. Penner JA, Kelly PE: Management of patients with factor VIII or IX inhibitors. Sem Thromb Hemostasis 1:386-399, 1975 5. Ehrenforth S, Kreuz W, Scharrer I, et al: Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 339:594-598, 1992 6. McMillan CW, Shapiro SS, Whitehurst D, et al: The natural history of factor VIII inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors. Blood 71:344-348, 1988 7. Addiego JE Jr., Gomperts E, Liu S, et al: Treatment of hemophilia A with a highly purified Factor VIII concentrate prepared by Anti-FVIIIc immunoaffinity chromatography. Thrombosis and Haemostasis 67:19-27, 1992 8. Abildgaard CF, Simone JV, Corrigan JJ, et al: Treatment of hemophilia with glycine-precipitated Factor VIII. New Eng J Med 275:471-475, 1966 9. Schimpf K, Rothman P, Zimmermann K: Factor VIII dosis in prophylaxis of hemophilia A; A further controlled study in Proc XIth Cong W.F.H. Kyoto, Japan, Academic Press, 1976, pp 363-366 10. Gill FM: The Natural History of Factor VIII Inhibitors in Patients with Hemophilia A. Hoyer LW (ed), Factor VIII Inhibitors, N.Y. AR Liss, 1984, pp 19-29 11. Rasi V, Ikkala E: Haemophiliacs with factor VIII inhibitors in Finland: prevalence, incidence and outcome. Br J Haematol 76:369-371, 1990 12. Lusher JM, Salzman PM: Viral Safety and Inhibitor Development Associated with Factor VIIIC Ultra-Purified From Plasma in Hemophiliacs Previo usly Unexposed to Factor VIIIC Concentrates. Seminars in Hematology 27:1-7, 1990

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS General The clinical response to Kogenate FS may vary. If bleeding is not controlled with the recommended dose, the plasma level of factor VIII should be determined and a sufficient dose of Kogenate FS should be administered to achieve a satisfactory clinical response. If the patient's plasma factor VIII level fails to increase as expected or if bleeding is not controlled after the expected dose, the presence of an inhibitor (neutralizing antibodies) should be suspected and appropriate testing performed. [See Monitoring Laboratory Tests below.] Anaphylaxis And Severe Hypersensitivity Reactions Allergic-type hypersensitivity reactions including anaphylaxis have been reported with Kogenate FS and have manifested as pruritus, rash, urticaria, hives, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, discomfort (generalized) and fatigue. Discontinue Kogenate FS if symptoms occur and seek immediate emergency treatment. Kogenate FS contains trace amounts of mouse immunoglobulin G (MuIgG) and hamster (BHK) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. Neutralizing Antibodies Patients treated with antihemophilic factor (AHF) products should be carefully monitored for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests.6 Inhibitors have been reported following administration of Kogenate FS predominantly in previously untreated patients. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor VIII inhibitor concentration should be performed. [See Monitoring Laboratory Tests below] Monitoring Laboratory Tests Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained, when clinically indicated. [See DOSAGE AND ADMINISTRATION] Monitor for development of factor VIII inhibitors. Perform assay to determine if factor VIII inhibitor is present. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with the expected dose of Kogenate FS. Use Bethesda Units (BU) to titer inhibitors. If the inhibitor is less than 10 BU per mL, the administration of additional Kogenate FS concentrate may neutralize the inhibitor, and may permit an appropriate hemostatic response. Adequate hemostasis may not be achieved if inhibitor titers are above 10 BU per mL. The inhibitor titer may rise following Kogenate FS infusion as a result of an anamnestic response to factor VIII. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents. Patient Counseling Information See Patient Product Information and Instructions for Use Advise patients to report any adverse reactions or problems following Kogenate FS administration to their physician or healthcare provider. Allergic-type hypersensitivity reactions have been reported with Kogenate FS. Warn patients of the early signs of hypersensitivity reactions [including hives (rash with itching), generalized urticaria, tightness of the chest, wheezing, hypotension] and anaphylaxis. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment with resuscitative measures such as the administration of epinephrine and oxygen. In clinical studies with Kogenate FS, a 15% incidence of inhibitor development was observed in PUPs/MTPs and zero de novo inhibitors were observed with the PTPs. Inhibitor formation may occur at any time in the treatment of a patient with hemophilia A. Advise patients to contact their physician or treatment center for further treatment and/or assessment, if they experience a lack of clinical response to factor VIII replacement therapy, as this may be a manifestation of an inhibitor. Advise patients to consult with their healthcare provider prior to travel. While traveling advise patients to bring an adequate supply of Kogenate FS based on their current regimen of treatment. Nonclinical Toxicology Preclinical studies evaluating Kogenate FS in hemophilia A with mice, rats, rabbits, and dogs demonstrated safe and effective restoration of hemostasis. Doses several fold higher than the recommended clinical dose (related to body weight) did not demonstrate any acute or subacute toxic effect for Kogenate FS in laboratory animals. Carcinogenesis, Mutagenesis, Impairment Of Fertility No studies have been conducted with Kogenate FS to assess its mutagenic or carcinogenic potential and impairment of fertility. Kogenate FS has been shown to be comparable to the predecessor product with respect to its biochemical and physiochemical properties, as well as its non-clinical in vivo pharmacology and toxicology. By inference, the predecessor product and Kogenate FS would be expected to have equivalent mutagenic and carcinogenic potential. The predecessor product did not demonstrate reverse mutation or chromosomal aberrations at doses substantially greater than the maximum expected clinical dose. In vivo evaluation with the predecessor product in animals using doses ranging between 10 and 40 times the expected clinical maximum also indicated that the predecessor product did not possess a mutagenic potential. Long-term investigations of carcinogenic potential in animals have not been performed due to the immune response to heterologous proteins in all non-human mammalian species. Use In Specific Populations Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with Kogenate FS. It is also not known whether Kogenate FS can cause fetal harm when administered to a pregnant woman or affect reproduction capacity. Kogenate FS should be used during pregnancy only if clinically needed. Labor And Delivery There is no information available on the effect of factor VIII replacement therapy on labor and delivery. Kogenate FS should be used only if clinically needed. Nursing Mothers It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if Kogenate FS is administered to nursing mothers. Kogenate FS should be given to nursing mothers only if clinically needed. Pediatric Use Safety and efficacy studies have been performed in previously untreated and minimally treated pediatric patients. Children in comparison to adults present higher factor VIII clearance values and thus lower recovery of factor VIII. This may be explained by differences in body composition7 and should be taken into account when dosing or following factor VIII levels in such a population. [See CLINICAL PHARMACOLOGY] Routine prophylactic treatment in children ages 0-2.5 years with no pre-existing joint damage has been shown to reduce spontaneous joint bleeding and the risk of joint damage. This data can be extrapolated to ages > 2.5-16 years for children who have no existing joint damage. [See Clinical Studies] Geriatric Use Clinical studies with Kogenate FS did not include patients aged 65 and over. Dose selection for an elderly patient should be individualized. REFERENCES 6. Kasper CK: Complications of hemophilia A treatment: factor VIII inhibitors. Ann NY Acad Sci 614:97-105, 1991. 7. Barnes C, Lillicrap D, Pazmino-Canizares J, et al: Pharmacokinetics of recombinant factor VIII (Kogenate-FS®) in children and causes of inter-patient pharmacokinetic variability. Haemophilia 12 (Suppl. 4): 40-49, 2006.

WARNINGS None. PRECAUTIONS General Helixate® FS Antihemophilic Factor (Recombinant) is intended for the treatment of bleeding disorders arising from a deficiency in FVIII. This deficiency should be proven prior to administering Helixate FS (antihemophilic factor (recombinant)) . The development of circulating neutralizing antibodies to FVIII may occur during the treatment of patients with hemophilia A. Inhibitor formation is especially common in young children with severe hemophilia during their first years of treatment, or in patients of any age who have received little previous treatment with FVIII. Nonetheless, inhibitor formation may occur at any time in the treatment of a patient with hemophilia A. Patients treated with any AHF preparation, including Helixate FS (antihemophilic factor (recombinant)) , should be carefully monitored for the development of antibodies to FVIII by appropriate clinical observation and laboratory tests, according to the recommendation of the patient's hemophilia treatment center. Among patients treated with antihemophilic factor concentrates, cases of hypotension, urticaria, and chest tightness in association with hypersensitivity reactions have been reported in the literature.11-13 Very rare cases of allergic and anaphylactic reactions have been reported with the predecessor product HELIXATE® Antihemophilic Factor (Recombinant), particularly in very young patients or patients who have previously reacted to other FVIII concentrates (see ADVERSE REACTIONS - Post-marketing experience). Serious anaphylactic reactions require immediate emergency treatment with resuscitative measures such as the administration of epinephrine and oxygen. Formation of Antibodies to Mouse and Hamster Protein Assays to detect seroconversion to mouse and hamster protein were conducted on all patients in clinical studies. No patient has developed specific antibodies to these proteins after commencing study, and no animal protein associated serious allergic reactions have been observed with rFVIII-FS infusions. Although no such reactions were observed, patients should be made aware of the possibility of a hypersensitivity reaction to mouse and/or hamster protein, and alerted to the early signs of such a reaction (e.g., hives, localized or generalized urticaria, wheezing, and hypotension). Patients should be advised to discontinue use of the product and contact their physician if such symptoms occur. Carcinogenesis, Mutagenesis, and Impairment of Fertility In vitro evaluation of the mutagenic potential of rFVIII failed to demonstrate reverse mutation or chromosomal aberrations at doses substantially greater than the maximum expected clinical dose. In vivo evaluation of rFVIII in animals using doses ranging between 10 and 40 times the expected clinical maximum also indicated that rFVIII does not possess a mutagenic potential. Long-term investigations of carcinogenic potential in animals have not been performed. Pediatric Use Helixate® FS Antihemophilic Factor (Recombinant) is appropriate for use in pediatric patients of all ages, including neonates, infants, children, and adolescents. Safety and efficacy studies have been performed in previously untreated and minimally treated pediatric patients (n=62). Helixate FS (antihemophilic factor (recombinant)) is similar to HELIXATE in its biological activity and may be used in pediatric patients in the same manner as HELIXATE. Geriatric Use Clinical studies with Helixate FS (antihemophilic factor (recombinant)) did not include sufficient numbers of patients aged 65 and over to be able to determine whether they respond differently from younger patients. However, clinical experience with HELIXATE and other AHF products has not identified differences between the elderly and younger patients. As with any patient receiving Helixate FS (antihemophilic factor (recombinant)) , dose selection for an elderly patient should be individualized. Pregnancy Category C Animal reproduction studies have not been conducted with Helixate FS (antihemophilic factor (recombinant)) . It is also not known whether Helixate FS (antihemophilic factor (recombinant)) can cause fetal harm when administered to a pregnant woman or affect reproduction capacity. Helixate FS (antihemophilic factor (recombinant)) should be used during pregnancy and lactation only if clearly indicated. REFERENCES 11. Brettler DB, Forsberg AD, Levine PH, et al: The use of porcine factor VIII concentrate (Hyate:C) in the treatment of patients with inhibitor antibodies to factor VIII. A multicenter US experience. Arch Intern Med 149(6): 1381-5, 1989. 12. Eyster ME, Bowman HS, Haverstick JN: Adverse reactions to factor VIII infusions. Ann Intern Med 87(2):248, 1977. 13. Brettler DB, Levine PH: Factor concentrates for treatment of hemophilia: which one to choose? Blood 73(8):2067-73, 1989.

WARNINGS Monoclate-P® is made from human blood. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. Because Monoclate-P® is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current viral infections and inactivating and/or removing certain viruses during manufacture (see DESCRIPTION section for viral reduction measures). The manufacturing procedure for Monoclate-P® includes processing steps designed to reduce further the risk of viral transmission. Stringent procedures utilized at plasma collection centers, plasma testing laboratories, and fractionation facilities are designed to reduce the risk of viral transmission. The primary viral reduction step of the Monoclate-P® manufacturing process is the heat treatment of the purified, stabilized aqueous solution at 60°C for 10 hours. In addition, the purification procedure (several precipitation steps) used in the manufacture of Monoclate-P® also provides viral reduction capacity. Despite these measures, such products may still potentially contain human pathogenic agents, including those not yet known or identified. Thus the risk of transmission of infectious agents can not be totally eliminated. Any infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to CSL Behring at 1-866-915- 6958 (in the U.S. or Canada). Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections (see PATIENT INFORMATION). PRECAUTIONS General Most Antihemophilic Factor (Human) concentrates contain naturally occurring blood group specific antibodies. However, the processing of Monoclate-P® significantly reduces the presence of blood group specific antibodies in the final product. Nevertheless, when large or frequently repeated doses of product are needed, patients should be monitored by means of hematocrit and direct Coombs tests for signs of progressive anemia. Formation Of Antibodies To Mouse Protein Although no hypersensitivity reactions have been observed, because Monoclate-P® contains trace amounts of mouse protein ( ≤ 50 ng per 100 I.U. of AHF), the possibility exists that patients treated with Monoclate-P® may develop hypersensitivity to the mouse proteins. Pregnancy Category C Animal reproduction studies have not been conducted with Monoclate-P®. It is also not known whether Monoclate-P® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Monoclate-P® should be given to a pregnant woman only if clearly needed. Pediatric Use The safety and effectiveness of Monoclate-P® for the treatment of hemophilia A has been demonstrated in 33 pediatric patients. As in adults, pediatric patients should be dosed based upon weight (see DOSAGE AND ADMINISTRATION). Geriatric Use Clinical studies of Monoclate-P® did not include suffi cient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, refl ecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Dosing should be appropriate to the clinical situation.

WARNINGS Koate-DVI is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Despite these measures, because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically the Creutzfeldt-Jakob disease (CJD) agent. There is also the possibility that unknown infectious agents may be present in such products. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Talecris Biotherapeutics, Inc. [1-800-520-2807]. The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering it to a patient. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly hepatitis C. It is emphasized that hepatitis B vaccination is essential for patients with hemophilia and it is recommended that this be done at birth or diagnosis.8,9 Hepatitis A vaccination is also recommended for hemophilic patients who are hepatitis A seronegative. PRECAUTIONS General Koate (antihemophilic factor) -DVI is intended for treatment of bleeding disorders arising from a deficiency in factor VIII. This deficiency should be proven prior to administering Koate (antihemophilic factor) -DVI. Administer within 3 hours after reconstitution. Do not refrigerate after reconstitution. Administer only by the intravenous route. Filter needle should be used prior to administering. Koate (antihemophilic factor) -DVI contains levels of blood group isoagglutinins which are not clinically significant when controlling relatively minor bleeding episodes. When large or frequently repeated doses are required, patients of blood groups A, B, or AB should be monitored by means of hematocrit for signs of progressive anemia, as well as by direct Coombs' tests. Product administration and handling of the infusion set and needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in sharps container after single use. Discard all equipment including any reconstituted Koate (antihemophilic factor) -DVI product in accordance with biohazard procedures. Pregnancy Category C Animal reproduction studies have not been conducted with Koate (antihemophilic factor) -DVI. It is also not known whether Koate (antihemophilic factor) -DVI can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Koate (antihemophilic factor) -DVI should be given to a pregnant woman only if clearly needed. Pediatric Use Koate (antihemophilic factor) -DVI has not been studied in pediatric patients. Koate-HP, solvent/detergent treated Antihemophilic Factor (Human), has been used extensively in pediatric patients. Spontaneous adverse event reports with Koate (antihemophilic factor) -HP for pediatric use were within the experience of those reports for adult use. REFERENCES 8. National Hemophilia Foundation Medical and Scientific Advisory Council. Hemophilia Information Exchange–AIDS Update: Recommendations concerning AIDS and the treatment of hemophilia HIV infection. Section I.G. (Rev. Jan., 1988). 9. Safety of therapeutic products used for hemophilia patients. MMWR 37(29):441–4, 449–50, 1988.

WARNINGS No information provided. PRECAUTIONS General Identification of the clotting defect as a Factor VIII deficiency is essential before the administration of Antihemophilic Factor (Recombinant), Bioclate (antihemophilic factor) TM is initiated. No benefit may be expected from this product in treating other deficiencies. The formation of neutralizing antibodies, inhibitors, to factor VIII is a known complication in the management of individuals with hemophilia A. The reported prevalence of these anti-bodies in patients receiving plasma derived AHF is 10-20%3, 4, 5, 6, 7 10, 11, 12. These inhibitors are invariably IgG immunoglobulins, the factor VIII procoagulant inhibitory activity of which is expressed as Bethesda Units (B.U.) per mL of plasma or serum3, 4, 5, 6, 7. Over the investigational period, none of the 65 previously treated individuals, without an inhibitor at entry into the study, developed an inhibitor. In the previously untreated patient group there were 66 patients with factor VIII levels less than or equal to 2% who were tested for inhibitor after treatment with Bioclate (antihemophilic factor) TM rAHF. Of this group 12 individuals developed detectable inhibitor and of these, 3 patients showed a titer greater than 10 B.U. The true immunogenicity of Antihemophilic Factor (Recombinant), Bioclate (antihemophilic factor) TM is uncertain at this time. Patients treated with rAHF should be carefully monitored for the development of antibodies to rAHF by appropriate clinical observations and laboratory tests. Formation of Antibodies to Mouse, Hamster or Bovine Protein As Antihemophilic Factor (Recombinant), Bioclate (antihemophilic factor) TM contains trace amounts of mouse protein (maximum of 0.1 ng/IU rAHF), hamster protein (maximum of 1 ng CHO protein/IU rAHF), and bovine protein (maximum of 1 ng BSNIU rAHF), the remote possibility exists that patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. Information for Patients Although allergic type hypersensitivity reactions were not observed in any patient receiving Bioclate (antihemophilic factor) TM on study, such reactions are theoretically possible. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physician if these symptoms occur. Laboratory Tests Although dosage can be estimated by the calculations which follow, it is strongly recommended that whenever possible, appropriate laboratory tests be performed on the patients plasma at suitable intervals to assure that adequate AHF levels have been reached and are maintained. If the patients plasma AHF fails to reach expected levels or if bleeding is not controlled after adequate dosage, the presence of inhibitor should be suspected. By performing appropriate laboratory procedures, the presence of an inhibitor can be demonstrated and quantified in terms of AHF International Units neutralized by each mL of plasma or by the total estimated plasma volume. If the inhibitor is present at levels less than 10 Bethesda Units per mL, administration of adthtional AHF may neutralize the inhibitor. Thereafter the administra tion of additional AHF International Units should elicit the predicted response. The control of AHF levels by laboratory assay is necessary in this situation. Inhibitor titers above 10 Bethesda Units per mL may make hemostasis control with AHF either impossible or impractical because of the very large dose required. In addition, the inhibitor titer may rise following AHF infusion because of an anamnestic response to the AHF antigen. Carcinogenesis, Mutagenesis, Impairment of Fertility Bioclate (antihemophilic factor) † was tested for mutagenicity at doses considerably exceeding plasma concentrations of rAHF in vitro and at doses up to ten times the expected maximum clinical dose in vivo, and did not cause reverse mutations, chromosomal aberrations, or an increase in micronuclei in bone marrow polychromatic erythrocytes. Long term studies in animals have not been performed to evaluate carcinogenic potential. Pediatric Use Bioclate (antihemophilic factor) TM is appropriate for use in children of all ages, including the newborn. Safety and efficacy studies have been performed in both previously treated (n = 23) and previously untreated (n = 75) children. (See CLINICAL PHARMACOLOGY). Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Antihemophilic Factor (Recombinant). It is not known whether Antihemophilic Factor (Recombinant) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Antihemophilic Factor (Recombinant) should be given to a pregnant woman only if clearly needed.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions Anaphylaxis and severe hypersensitivity reactions are possible with ALPHANATE. Early signs of allergic reactions, which can progress to anaphylaxis, may include angioedema, chest tightness, hypotension, rash, nausea, vomiting, paresthesia, restlessness, wheezing and dyspnea. Discontinue use of ALPHANTE if hypersensitivity symptoms occur, and initiate appropriate treatment. Neutralizing Antibodies Development of procoagulant activity-neutralizing antibodies (inhibitors) has been detected in patients receiving FVIII-containing products. Carefully monitor patients treated with AHF products for the development of FVIII inhibitors by appropriate clinical observations and laboratory tests. No specific studies have been conducted with ALPHANATE to evaluate inhibitor formation. If expected plasma FVIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an appropriate assay that measures FVIII inhibitor concentration. Thromboembolic Events Thromboembolic events have been reported in von Willebrand Disease patients receiving replacement therapy with Antihemophilic Factor/von Willebrand Factor Complexes, especially in those with known risk factors for thrombosis including but not limited to elderly age, previous thrombosis, metabolic syndrome, cancer, surgery, oral contraceptive and hormone therapy, diabetes, hypertension, hyperlipidemia, smoking, and pregnancy.9 Monitor plasma levels of VWF:RCo and FVIII activities to avoid sustained excessive VWF and FVIII activity levels (greater than 150 IU/dL), which may increase the risk of thrombotic events, during continued treatment of replacement therapy with Antihemophilic Factor/von Willebrand Factor Complexes. Consider antithrombotic measures in VWD patients at risk for thrombosis [see ADVERSE REACTIONS]. Intravascular Hemolysis ALPHANATE contains blood group specific isoagglutinins. Monitor the patient for signs of intravascular hemolysis and decreasing hematocrit when large and/or frequent doses of Antihemophilic Factor/von Willebrand Factor Complexes are required in patients of blood groups A, B, or AB, as cases of acute hemolytic anemia, increased bleeding tendency or hyperfibrinogenemia have been reported. These events typically subside after cessation of the factor concentrate infusion.10 Consider alternative therapy should this condition worsen despite discontinuation of ALPHANATE. Vasomotor Reactions Rapid administration of a FVIII concentrate may result in vasomotor reactions. Do not administer ALPHANATE at a rate exceeding 10 mL/minute. Transmissible Infectious Agents Because ALPHANATE is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob Disease (vCJD) agent and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain virus infections, and by inactivating and/or removing certain viruses during manufacturing. [see DESCRIPTION]. Monitoring Laboratory Tests Monitor for development of FVIII and VWF inhibitors. Perform appropriate assays to determine if FVIII and/or VWF inhibitor(s) are present if bleeding is not controlled with expected dose of ALPHANATE. Monitor plasma levels of VWF:RCo and FVIII activities to avoid sustained excessive VWF and FVIII activity levels (greater than 150 IU/dL), which may increase the risk of thrombotic events, particularly in patients with known risk factors. Use In Specific Populations Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with ALPHANATE. It is also not known whether ALPHANATE can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. ALPHANATE should be given to a pregnant woman only if clearly needed. Labor And Delivery No human or animal data. Use only if clearly needed. Nursing Mothers No human or animal data. Use only if clearly needed. Pediatric Use Hemophilia A A total of 21 children (ages 7-16) were included in clinical trials with ALPHANATE. Subjects received ALPHANATE weekly for prophylaxis or suspected bleeds. They were successfully treated for 1499 bleeding episodes or as prophylaxis to prevent them (e.g., pain in the joint). The median number of units needed to treat the bleeds was 420 IU, with a range of 210 to 1620 IU. Adult and pediatric subjects did not differ in their response to treatment. Von Willebrand Disease The hemostatic efficacy of ALPHANATE has been studied in 20 pediatric subjects (ages 7-18) with VWD. Based on the data from a subset of these subjects, age had no effect on the pharmacokinetics of VWF:RCo. Adult and pediatric subjects did not differ in their response to treatment. Geriatric Use No human or animal data. Use only if clearly needed. REFERENCES 9. Coppola, A., Franchini, M., Makris M. Santagostino, E. Minno, G.DI, Mannucci, P.M. Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies. Haemophilia 2012; 18, e173-e187. 10. Soni, N.S., Patel A.R., Vohra, R.M., Shah P.C. Hemophiliac with Hemolytic Anemia resulting from Factor VIII Concentrate. Acta Haemato 1977; 58:294-297.